Novel bicyclic heterocyclic compound

ABSTRACT

The invention provides a compound for the treatment or prophylaxis of pathology involving SNS, specifically diseases such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis and the like. The compound is represented by formula (1) or a pharmaceutically acceptable salt thereof wherein R 1  is a hydrogen atom or the like, L is a single bond, —O— or the like, R 2  is a phenyl group or the like, X is a carbon atom or a nitrogen atom, and R 3 , R 4 , R 5a , R 5b , R 6  and R 7  are each independently a substituted or unsubstituted alkyl group or the like:

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of copending U.S. patent application Ser. No. 13/141,301, filed on Aug. 17, 2011, which is the U.S. national phase of International Patent Application No. PCT/JP2009/071529, filed on Dec. 25, 2009, which claims priority to Japanese Patent Application No. 2008-332796, filed on Dec. 26, 2008.

TECHNICAL FIELD

The present invention relates to a drug for the treatment or prophylaxis of pathology in general in which SNS (sensory neuron specific sodium channel) is involved, which comprises a novel compound having a benzimidazole or imidazopyridine skeleton as a bicyclic heterocycle or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the present invention relates to a drug for the treatment or prophylaxis of diseases such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis and the like.

BACKGROUND ART

In 1952, Hodgkin and Huxley showed that the main body of neural activity is an Na channel, after which Na channel blockers have been developed as antiarrhythmic or topical anesthetics. In 1961, lidocain, which is one of the Na channel blockers, was found to provide an analgesic effect, and clinical application thereof as an analgesic was started. However, since Na channel is also present in normeural tissues such as muscle, heart and the like, side effects by systemic administration remained as a problem.

With the advance of molecular biology, subtypes of Na channel have been elucidated one after another, and Na channel α subunit that forms pore is known to include 10 kinds at present. A sensory neuron specific sodium channel (sensory nerve-specific Na channel), i.e., SNS, is one of such Na channel α subunits, is a tetrodotoxin (TTX)-resistant Na channel localized in the small diameter cell (C fiber) of dorsal root ganglion involved in nerval perception, and is also called SCN10A, PN3 or NaV1.8 (non-patent documents 1, 2). It has been reported that SNS knockout mouse is insensitive to mechanical stimulations, and administration of antisense to SNS to neuropathic pain or inflammatory pain models attenuates hypersensitivity and abnormal perception.

Therefore, an SNS inhibitor is considered to provide a therapeutic or prophylactic drug showing an analgesic effect for diseases such as neuropathic pain, nociceptive pain and the like, which accompany pain, numbness, burning sensation, dull pain and the like, each involving C fiber. Moreover, since SNS is not expressed in normeural tissues and central nervous system, a medicament that selectively inhibits SNS is considered to be a medicament free of side effects derived from normeural tissues or central nervous system.

In dysuria, moreover, it has been clarified that frequent urination, its main symptom, is caused by overactivity of the C fiber; in other words, dysfunction of afferent sensory nervous pathway from the lower urinary tract is involved in overactive bladder and cystalgia, and suppression of C fiber sensory nerve from the bladder is effective thereon (non-patent document 3). Therefore, a medicament that inhibits SNS mainly causing the neural activity of C fiber is expected to be a therapeutic or prophylactic drug for dysuria, which has a novel point of action.

On the other hand, a recent report has documented that SNS found only in C fiber is ectopically expressed in cerebellar Purkinje cell of multiple sclerosis patients, and is involved in the occurrence of an abnormal firing pattern in the cerebellum (non-patent document 4). As such, an SNS inhibitor is expected to be a first therapeutic or prophylactic drug toward the induction of symptoms caused by abnormal firing associated with SNS expression in the cerebellar neuron, such as ataxia and the like in multiple sclerosis.

The following shows the actual treatment state of the aforementioned diseases in clinical practice.

(1) Neuropathic Pain

Neuropathic pain refers to a pain including spontaneous pain and chronic pain developed by nerve damage or nerve stimulation even when trauma is absent and tissue inflammation is absent after complete recovery. Examples thereof include neuralgia after lumbar operation, diabetic neuropathy, neuralgia after herpes zoster, reflex sympathetic dystrophy, phantom limb pain, spinal cord damage, late stage carcinomatous pain, and prolonged postoperative pain. NSAIDS (non-steroidal anti-inflammatory drugs) such as aspirin and the like are completely ineffective for neuropathic pain, and opioids such as morphine and the like are problematic in drug resistance and induction of psychological symptom.

At present, a sole medicament in the market, which is allegedly effective for neuropathic pain, is mexiletine applicable to diabetic neuropathy. Since mexiletine does not have selectivity to Na channel, though it provides an analgesis effect, side effects are feared and administration at a high dose has been reported to be unavailable. Some other medicaments are clinically applied as aids. Examples thereof include antidepressant (sulpiride, trazodone, fluvoxatine, milnacipran), adrenaline agonist (clonidine, dexmedetomidine), NMDA receptor antagonists (ketamine hydrochloride, dextromethorphan), antianxiety drug (diazepam, lorazepam, etizolam, hydroxyzine hydrochloride), anticonvulsant (carbamazepine, phenyloin, sodium valproate, zonisamide), calcium antagonist (nifedipine, verapamil hydrochloride, lomerizine hydrochloride) and the like, all of which are used as aids. From the above, a therapeutic drug free of side effects derived from normeural tissue or central nervous system and specifically effective for pain is desired.

(2) Nociceptive Pain

Nociceptive pain refers to a pain caused by the activation of nociceptor (Aδ, C fiber) by mechanical, hyperthermic or chemical noxious stimulation due to tissue injury and the like. Nociceptor is sensitized by endogenous chemical stimulation (algetic substance) such as serotonin, substance P, bradykinin, prostaglandin and histamine. Examples of the nociceptive pain include lumbago, abdominal pain, and pain due to rheumatoid arthritis or osteoarthritis. In clinical practice, NSAIDS (acetylsalicylic acid, acetaminophen, diclofenac sodium, indomethacin, mofezolac, flurbiprofen, loxoprofen sodium, ampiroxicam), steroid drugs (prednisolone, methylprednisolone, dexamethasone, betamethasone), PGE₁ (prostaglandin E1) (alprostadil, lipo alprostadil, limaprost alprostadil) and PGI₂ (beraprost sodium) are used.

(3) Dysuria (Urinary Disturbance)

Dysuria is a disease mainly showing urinary frequency, urorrhea, feeling of residual urine and urodynia as main symptoms. At present, the main drug treatment of overactive bladder uses a muscarinic receptor inhibitor that suppresses the bladder parasympathetic nerve pathway. However, its limitation has also been clarified. Capsaicin and resinifera toxin, which are vanilloid receptor stimulants, have been reported to specifically act on C fiber to suppress its function. However, a medicament that acts on SNS localized in C fiber has not been found.

(4) Multiple Sclerosis

Multiple sclerosis is one kind of demyelination diseases, which shows scattered foci of demyelination in the white matter of the central nervous system, with various old and new lesions. The lesions appear more commonly in the white matter of lateral cerebral ventricle periphery, optic nerve, brain stem, spinal cord and the like. Histologically, myelin sheath is destroyed and axon and nerve cell are not damaged. As clinical symptoms, symptoms such as optic neuritis, double vision, eyeball motion impairments such as nystagmus, convulsive paralysis, painful tonic convulsive attack, Lhermitte's syndrome, ataxia, logopathy, bladder rectal disorder and the like appear in various combinations. The etiology thereof is unknown, though autoimmune disease theory, infection theory and the like are proposed. At present, an effective prophylactic or therapeutic drug for multiple sclerosis is highly desired.

Patent document 1 to be mentioned later relates to a selective modulator of CRF1 receptor and specifically describes a compound represented by the following formula (A) (Example 5, k). The compounds encompassed in the patent document characteristically have an amide bond in methylene on the imidazole ring, and are different from the compound of the present invention having an amino group in methylene on the imidazole ring. In addition, patent document 1 does not at all contain a description suggesting the present invention.

Patent document 2 to be mentioned later relates to a Rho kinase inhibitor, and specifically describes a compound represented by the following formula (B) (Example 321). The compounds encompassed in the patent document do not have a substituent on the nitrogen atom of imidazole ring, and are different from the compound of the present invention essential having the substituent. In addition, patent document 2 does not at all contain a description suggesting the present invention.

DOCUMENT LIST Patent Document

-   Patent Document 1: WO 02/28839 -   Patent Document 2: WO 2009/79011

Non-Patent Document

-   non-Patent Document 1: Nature 379: 257, 1996 -   non-Patent Document 2: Pain 78: 107, 1998 -   non-Patent Document 3: Urology 57: 116, 2001 -   non-Patent Document 4: Brain Research 959: 235, 2003

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The problem of the present invention is to provide a drug for the prophylaxis or treatment of pathology in general in which SNS is involved, specifically, diseases such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis and the like.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt to solve the aforementioned problem and found that a bicyclic compound having an imidazole ring or a pharmaceutically acceptable salt thereof inhibits TTX resistant Na channel in human SNS gene expressing cell, namely, has an SNS inhibitory activity, and is useful as a therapeutic or prophylactic drug for diseases such as a neuropathic pain, a nociceptive pain, dysuria, multiple sclerosis and the like, which resulted in the completion of the present invention.

Accordingly, the present invention provides the following.

-   [1] a compound represented by the following formula (1) or a     pharmaceutically acceptable salt thereof (hereinafter sometimes     referred to as “the compound of the present invention”):     a compound represented by

wherein R¹ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms (R¹ can substitute the benzene ring or pyridine ring at any substitutable position thereon), L is a single bond, —O— or —CH₂O— (L can substitute the benzene ring or pyridine ring at any substitutable position thereon), R² is a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group, X is a carbon atom or a nitrogen atom, R³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered cycloalkenyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, R⁴ is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted 3- to 8-membered cycloalkyl group, R^(5a) and R^(5b) are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or R⁴ and R^(5a) are optionally bonded to form, together with the nitrogen atom that R⁴ is bonded to, a 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle (in this case, R^(5b) is a hydrogen atom), R⁶ and R⁷ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered cycloalkenyl group, a substituted or unsubstituted O-5 to 8-membered saturated aliphatic heterocyclic group, a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group, or R⁶ and R⁷ are optionally bonded to form, together with the nitrogen atom that they are bond to, a substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle, or a substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocycle (the saturated or unsaturated nitrogen-containing aliphatic heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 3 nitrogen atoms) (hereinafter sometimes referred to as “compound (1)”) or a pharmaceutically acceptable salt thereof;

-   [2] the compound of [1], which is represented by the following     formula (2):

wherein R¹, R², R³, R⁴, R^(5a), R^(5b), R⁶, R⁷, L and X are as defined in [1] (hereinafter sometimes referred to as “compound (2)”) or a pharmaceutically acceptable salt thereof; [3] the compound of [1], which is represented by the following formula (3):

wherein R¹, R², R³, R⁴, R^(5a), R^(5b), R⁶, R⁷, L and X are as defined in [1] (hereinafter sometimes referred to as “compound (3)”) or a pharmaceutically acceptable salt thereof; [4] the compound of any one of [1] to [3], wherein R² is a substituted or unsubstituted phenyl group, or a pharmaceutically acceptable salt thereof;

-   [5] the compound of any one of [1] to [4], wherein R³ is a     substituted or unsubstituted alkyl group having 1 to 6 carbon atoms,     a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a     substituted or unsubstituted 4- to 8-membered saturated aliphatic     heterocyclic group, or a substituted or unsubstituted 5- to     10-membered unsaturated aliphatic heterocyclic group, or a     pharmaceutically acceptable salt thereof;     [6] the compound of any one of [1] to [5], wherein R⁶ and R⁷ are     each independently a hydrogen atom, a substituted or unsubstituted     alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1     to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered     cycloalkyl group, a substituted or unsubstituted 4- to 8-membered     saturated aliphatic heterocyclic group, or a substituted or     unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic     group, or R⁶ and R⁷ are optionally bonded to form, together with the     nitrogen atom that they are bond to, a substituted or unsubstituted     4- to 8-membered saturated nitrogen-containing aliphatic     heterocycle, or a substituted or unsubstituted 5- to 10-membered     unsaturated nitrogen-containing aliphatic heterocycle (the saturated     or unsaturated nitrogen-containing aliphatic heterocycle contains 0     to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 3 nitrogen atoms),     or a pharmaceutically acceptable salt thereof;     [7] the compound of any one of [1] to [6], wherein R⁴ is a hydrogen     atom, or a substituted or unsubstituted alkyl group having 1 to 6     carbon atoms, or a pharmaceutically acceptable salt thereof; -   [8] the compound of any one of [1] to [7], wherein R^(5a) and R^(5b)     are each independently a hydrogen atom, or a substituted or     unsubstituted alkyl group having 1 to 6 carbon atoms, or a     pharmaceutically acceptable salt thereof; -   [9] the compound of any one of [1] to [8], wherein X is a carbon     atom, or a pharmaceutically acceptable salt thereof; -   [10] the compound of any one of [1] to [9], wherein R¹ is a hydrogen     atom or a halogen atom, or a pharmaceutically acceptable salt     thereof;     [11] the compound of any one of [1] to [10], wherein L is a single     bond, or a pharmaceutically acceptable salt thereof; -   [12] the compound of any one of [1] to [10], wherein L is —O—, or a     pharmaceutically acceptable salt thereof; -   [13] the compound of any one of [1] to [10], wherein L is —CH₂O—, or     a pharmaceutically acceptable salt thereof; -   [14]     N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}glycinamide, -   N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide, -   N²-{[1-cyclopropyl-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-cyclobutyl-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(4-chlorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(4-fluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(4-fluorophenoxy)-1-(3-methoxypropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(2-chloro-4-fluorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-(2-ethoxyethyl)-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-ethyl-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-(3-methoxypropyl)-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(4-methylphenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[5-chloro-1-(2-ethoxyethyl)-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,     or -   N²-{[5-chloro-6-(3,4-difluorophenyl)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,     or a pharmaceutically acceptable salt thereof; -   [15] a medicament comprising the compound of any one of [1] to -   [14] or a pharmaceutically acceptable salt thereof as an active     ingredient; -   [16] the medicament of [15], which is an agent for the prophylaxis     or treatment of neuropathic pain, nociceptive pain, dysuria or     multiple sclerosis; -   [17] a SNS inhibitor comprising the compound of any one of [1] to     [14] or a pharmaceutically acceptable salt thereof as an active     ingredient; -   [18] a pharmaceutical composition comprising the compound of any one     of [1] to [14] or a pharmaceutically acceptable salt thereof, and a     pharmaceutically acceptable carrier.

Effect of the Invention

The present invention provides an SNS inhibitor comprising a novel bicyclic compound or a pharmaceutically acceptable salt thereof. The SNS inhibitor of the present invention is useful as a drug for the treatment or prophylaxis of pathology in general in which SNS is involved, and is specifically applicable to patients with neuropathic pain, nociceptive pain, dysuria, multiple sclerosis and the like.

DESCRIPTION OF EMBODIMENTS

In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The “alkyl group” means a straight chain or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl group, ethyl group, propyl group (1-propyl group), isopropyl group (2-propyl group), butyl group (1-butyl group), sec-butyl group (2-butyl group), isobutyl group (2-methyl-1-propyl group), tert-butyl group (2-methyl-2-propyl group), pentyl group (1-pentyl group), hexyl group (1-hexyl group) and the like. The alkyl group is preferably an alkyl group having 1 to 4 carbon atoms.

The “haloalkyl group” means a straight chain or branched alkyl group having 1 to 6 carbon atoms, which is substituted by the same or different 1 to 5 halogen atoms, and specific examples thereof include trifluoromethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group and the like. The haloalkyl group is preferably a haloalkyl group alkyl group having 1 to 4 carbon atoms.

The “alkenyl group” means a straight chain or branched alkenyl group having 2 to 6 carbon atoms, and specific examples thereof include vinyl group, 1-propenyl group, 2-propenyl group, 1-methylvinyl group, 1-butenyl group, 1-ethylvinyl group, 1-methyl-2-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 1-hexenyl group and the like. The alkenyl group is preferably an alkenyl group having 2 to 4 carbon atoms.

The “alkynyl group” means a straight chain or branched alkynyl group having 2 to 6 carbon atoms, and specific examples thereof include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group and the like. The alkynyl group is preferably an alkynyl group having 2 to 4 carbon atoms.

The “alkoxy group” means a straight chain or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include methoxy group, ethoxy group, propoxy group, 1-methylethoxy group, butoxy group, 1-methylpropoxy group, 2-methylpropoxy group, 1,1-dimethylethoxy group, pentyloxy group, hexyloxy group and the like. The alkoxy group is preferably an alkoxy group having 1 to 4 carbon atoms.

The “haloalkoxy group” means a straight chain or branched alkoxy group having 1 to 6 carbon atoms, which is substituted by the same or different 1 to 5 halogen atoms, and specific examples thereof include trifluoromethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 2-chloroethoxy group, pentafluoroethoxy group, 3,3,3-trifluoropropoxy group and the like. The haloalkoxy group is preferably a haloalkoxy group having 1 to 4 carbon atoms.

The “cycloalkyl group” means a 3- to 8-membered monocyclic or bicyclic cycloalkyl group, and specific examples thereof include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. The cycloalkyl group is preferably a 4- to 6-membered cycloalkyl group.

The “cycloalkenyl group” means a 4- to 8-membered monocyclic or bicyclic cycloalkenyl group, and specific examples thereof include cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group and cyclooctenyl group. The position of double bond on the ring is not particularly limited. The cycloalkenyl group is preferably a 5- or 6-membered cycloalkenyl group.

The “saturated aliphatic heterocyclic group” means a O-5 to 8-membered monocyclic or bicyclic saturated aliphatic heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (provided that the numbers of the oxygen atom and sulfur atom contained in the saturated aliphatic heterocycle are each up to 2). The position of the hetero atom is not particularly limited as long as the saturated aliphatic heterocyclic group is chemically stable. Specific examples thereof include azetidinyl group, pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group, azepanyl group, azocanyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydropyranyl group, morpholinyl group, morpholino group, thiomorpholinyl group, 1,4-dioxanyl group, 1,2,5-thiadiazinyl group, 1,4-oxazepanyl group, 1,4-diazepanyl group and the like.

The “unsaturated aliphatic heterocyclic group” means a 5- to 10-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic group containing 1 to 3 double bonds and 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (provided that the numbers of the oxygen atom and sulfur atom contained in the unsaturated aliphatic heterocycle are each up to 2). The positions of the hetero atom and double bond are not particularly limited as long as the unsaturated aliphatic heterocyclic group is chemically stable. Specific examples thereof include pyrrolinyl group, imidazolinyl group, tetrahydroisoquinolyl group and the like, and 2-pyrrolinyl group and 2-imidazolinyl group are preferable.

The “saturated nitrogen-containing aliphatic heterocycle” means a 4- to 8-membered monocyclic or bicyclic saturated aliphatic heterocycle containing at least one nitrogen atom and optionally further containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (provided that the numbers of the oxygen atom and sulfur atom contained in the saturated aliphatic heterocycle are each up to 2). The position of the hetero atom is not particularly limited as long as the saturated nitrogen-containing aliphatic heterocycle is chemically stable. Specific examples thereof include azetidine ring, pyrrolidine ring, imidazolidine ring, pyrazolidine ring, piperidine ring, piperazine ring, azepane ring, azocane ring, morpholine ring, thiomorpholine ring, oxazolidine ring, thiazolidine ring and the like.

The “unsaturated nitrogen-containing aliphatic heterocycle” means a 4- to 8-membered monocyclic or bicyclic unsaturated aliphatic heterocycle containing at least one nitrogen atom and optionally further containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (provided that the numbers of the oxygen atom and sulfur atom contained in the unsaturated aliphatic heterocycle are each up to 2). The position of the hetero atom is not particularly limited as long as the unsaturated nitrogen-containing aliphatic heterocycle is chemically stable. Specific examples thereof include pyrroline ring, piperidine ring, imidazoline ring, pyrazoline ring, oxazoline ring, thiazoline ring, tetrahydroquinoline ring, tetrahydroisoquinoline ring and the like.

The “aryl group” means a 6- to 10-membered monocyclic or bicyclic aryl group, and specific examples thereof include phenyl group, 1-naphthyl group, 2-naphthyl group and the like.

The “aromatic heterocyclic group” means a 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (provided that the numbers of the oxygen atom and sulfur atom contained in the aromatic heterocyclic group are each up to 2). The position of the hetero atom is not particularly limited as long as the aromatic heterocyclic group is chemically stable. Specific examples thereof include furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, triazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, oxadiazolyl group, triazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, indolyl group, quinolyl group, isoquinolyl group, quinazolinyl group, imidazo[2,1-b][1,3]thiazolyl group and the like.

The “alkylthio group” means a straight chain or branched alkylthio group having 1 to 6 carbon atoms, and specific examples thereof include methylthio group, ethylthio group, propylthio group, 1-methylethylthio group, butylthio group, 1-methylpropylthio group, 2-methylpropylthio group, 1,1-dimethylethylthio group, pentylthio group, hexylthio group and the like. The alkylthio group is preferably an alkylthio group having 1 to 4 carbon atoms.

Examples of the alkyl of the “alkylcarbonyl group” include those similar to the aforementioned alkyl group. Preferable examples of the alkylcarbonyl group include acetyl group, propionyl group, butyryl group and the like.

The “alkylcarbonyloxy group” means a group wherein the oxygen atom is bonded to the carbonyl carbon of the aforementioned “alkylcarbonyl group”.

Examples of the alkyl of the “alkylsulfonyl group” include those similar to the aforementioned “alkyl group”. Preferable examples of the alkylsulfonyl group include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group and the like.

Examples of the alkoxy of the “alkoxycarbonyl group” include those similar to the aforementioned “alkoxy group”. Preferable examples of the alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group and the like.

Examples of the alkyl group of the “amino group optionally substituted by one alkyl group or the same or different two alkyl groups”, “carbamoyl group optionally substituted by one alkyl group or the same or different two alkyl groups” and “sulfamoyl group optionally substituted by one alkyl group or the same or different two alkyl groups” include those similar to the aforementioned “alkyl group”.

Preferable examples of the “amino group optionally substituted by one alkyl group or the same or different two alkyl groups” include methylamino group, ethylamino group, propylamino group, dimethylamino group, diethylamino group, methylethylamino group and the like.

Preferable examples of the “carbamoyl group optionally substituted by one alkyl group or the same or different two alkyl groups” include methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, methylethylcarbamoyl group and the like.

Preferable examples of the “sulfamoyl group optionally substituted by one alkyl group or the same or different two alkyl groups” include methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, methylethylsulfamoyl group and the like.

Examples of the “alkoxycarbonyl group” of the “amidino group optionally substituted by one alkoxycarbonyl group or the same or different two alkoxycarbonyl groups” include those similar to the aforementioned “alkoxycarbonyl group”. Preferable examples of the “amidino group optionally substituted by one alkoxycarbonyl group or the same or different two alkoxycarbonyl groups” include methoxycarbonylamidino group, ethoxycarbonylamidino group, propoxycarbonylamidino group and the like.

The aryl group of the “aryloxy group”, “arylcarbonyl group” and “arylsulfonyl group” is as defined for the aforementioned “aryl group”.

The aromatic heterocyclic group of the “aromatic heterocyclyloxy group”, “aromatic heterocyclylcarbonyl group” and “aromatic heterocyclylsulfonyl group” is as defined for the aforementioned “aromatic heterocyclic group”.

The substituent for the “alkyl group”, “alkenyl group” and “alkynyl group” is selected from the group consisting of the following (i) to (v), and the same or different plural substituents may be present:

(i) a halogen atom, a hydroxyl group, a carboxyl group and a cyano group; (ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, and a substituted or unsubstituted sulfamoyl group; (iii) an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an alkylthio group and an alkylsulfonyl group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, an amino group optionally substituted by one alkyl group or the same or different two alkyl groups, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group]; (iv) a cycloalkyl group, a cycloalkenyl group, and a saturated or unsaturated aliphatic heterocyclic group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, an amino group optionally substituted by one alkyl group or the same or different two alkyl groups, a carbamoyl group optionally substituted by one alkyl group or the same or different two alkyl groups, an alkoxy group, a haloalkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkoxycarbonyl group, alkylcarbonyl group, alkylsulfonyl group and alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group and a carbamoyl group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group]; (v) an aryl group, an aromatic heterocyclic group, an aryloxy group, an aromatic heterocyclyloxy group, an arylcarbonyl group, an aromatic heterocyclylcarbonyl group, an arylsulfonyl group and an aromatic heterocyclylsulfonyl group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group and a haloalkoxy group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group].

The substituent for the “cycloalkyl group”, “cycloalkenyl group”, “saturated aliphatic heterocyclic group”, “unsaturated aliphatic heterocyclic group”, “saturated nitrogen-containing aliphatic heterocycle” and “unsaturated nitrogen-containing aliphatic heterocycle” is one substituent or the same or different two or more substituents, which are selected from the group consisting of the following (vi) to (x):

(vi) a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an oxo group, a thioxo group, and an amidino group optionally substituted by one alkoxycarbonyl group or the same or different two alkoxycarbonyl groups; (vii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, and a substituted or unsubstituted sulfamoyl group; (viii) an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an alkylthio group and an alkylsulfonyl group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group optionally substituted by one alkyl group or the same or different two alkyl groups, an alkoxy group optionally substituted by alkoxy group(s) and/or a carbamoyl group(s), a haloalkoxy group, an alkylthio group, an alkoxycarbonyl group, an optionally substituted aryloxy group, an optionally substituted aromatic heterocyclyloxy group, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group and optionally substituted amino group. Examples of the substituent for the aryloxy group, aromatic heterocyclyloxy group, aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group. Examples of the substituent for the amino group include an optionally substituted alkyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkylsulfonyl group, and a carbamoyl group optionally substituted by one alkyl group or the same or different two alkyl groups. Examples of the substituent for the alkyl group of the alkyl group, alkylcarbonyl group, alkylsulfonyl group and carbamoyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group and a carbamoyl group]; (ix) a cycloalkyl group, a cycloalkenyl group, and a saturated or unsaturated aliphatic heterocyclic group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, an amino group optionally substituted by one alkyl group or the same or different two alkyl groups, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group and a haloalkoxy group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group]; (x) an aryl group, an aromatic heterocyclic group, an aryloxy group, an aromatic heterocyclyloxy group, an arylcarbonyl group, an aromatic heterocyclylcarbonyl group, an arylsulfonyl group and an aromatic heterocyclylsulfonyl group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group and a haloalkoxy group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group].

The substituent for the “phenyl group”, “aryl group” and “aromatic heterocyclic group” is 1 to 5 substituents selected from the group consisting of the following (xi) to (xv):

(xi) a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a nitro group, a methylenedioxy group, an ethylenedioxy group and —(CH₂)_(n)— (n is an integer of 3 to 5); (xii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, and a substituted or unsubstituted sulfamoyl group; (xiii) an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an alkylthio group and an alkylsulfonyl group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, an amino group optionally substituted by one alkyl group or the same or different two alkyl groups, an optionally substituted alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkoxy group, aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group]; (xiv) a cycloalkyl group, a cycloalkenyl group, and a saturated or unsaturated aliphatic heterocyclic group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, an amino group optionally substituted by one alkyl group or the same or different two alkyl groups, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group and a haloalkoxy group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group]; (xv) an aryl group, an aromatic heterocyclic group, an aryloxy group, an aromatic heterocyclyloxy group, an arylcarbonyl group, an aromatic heterocyclylcarbonyl group, an arylsulfonyl group and an aromatic heterocyclylsulfonyl group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group and a haloalkoxy group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group].

The substituent for the “amino group”, “carbamoyl group” and “sulfamoyl group” is one substituent or the same or different two substituents, which are selected from the group consisting of the following (xvi)-(xviii):

(xvi) an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an alkylcarbonyl group, an alkylsulfonyl group and an alkoxycarbonyl group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, an amino group optionally substituted by one alkyl group or the same or different two alkyl groups, a carbamoyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a saturated or unsaturated aliphatic heterocyclic group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group]; (xvii) a cycloalkyl group, a cycloalkenyl group, and a saturated or unsaturated aliphatic heterocyclic group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, an amino group optionally substituted by one alkyl group or the same or different two alkyl groups, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group and a haloalkoxy group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group]; (xviii) an aryl group, an aromatic heterocyclic group, an arylcarbonyl group, an aromatic heterocyclylcarbonyl group, an arylsulfonyl group and an aromatic heterocyclylsulfonyl group [these groups are optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a carboxyl group, an amino group optionally substituted by one alkyl group or the same or different two alkyl groups, a carbamoyl group optionally substituted by one alkyl group or the same or different two alkyl groups, a sulfamoyl group optionally substituted by one alkyl group or the same or different two alkyl groups, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group and a haloalkoxy group. Examples of the substituent for the aryl group and aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group].

In addition, the two substituents for the “amino group”, “carbamoyl group” or “sulfamoyl group” are optionally bonded to form, together with the adjacent nitrogen atom, a 5- to 10-membered nitrogen-containing aliphatic heterocycle.

Examples of the nitrogen-containing aliphatic heterocycle include pyrrolidine ring, piperidine ring, an azepane ring, an azocane ring, a piperazine ring, a morpholine ring, a thiomorpholine ring and a tetrahydroisoquinoline ring. In addition, the nitrogen-containing aliphatic heterocycle is optionally substituted by one or more substituents selected from halogen, a hydroxyl group, a carboxyl group, an optionally substituted alkyl group, a haloalkyl group, an alkoxy group and a haloalkoxy group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group and a carbamoyl group.

In the compound of the present invention represented by the formula (1), each of the groups is preferably as follows.

R¹ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms, preferably a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms, more preferably a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms, more preferably a hydrogen atom or a halogen atom, particularly preferably a hydrogen atom. R¹ can be present on the benzene ring or pyridine ring at any substitutable position.

Specific examples of R¹ include a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, a trifluoromethyl group and the like. Among them, a hydrogen atom, a fluorine atom and a chlorine atom are preferable, and a hydrogen atom is more preferable.

L is a single bond, —O— or —CH₂O—, preferably, a single bond or —O—, more preferably —O—. L can be present on the benzene ring or pyridine ring at any substitutable position. When L is —CH₂O—, the oxygen atom of —CH₂O— is bonded to the benzene ring or pyridine ring, and the methylene chain is bonded to R².

R² is a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group, preferably a substituted or unsubstituted 6- to 10-membered aryl group, more preferably a substituted or unsubstituted phenyl group.

Preferable examples of the substituent of the aryl group or aromatic heterocyclic group for R² include a halogen atom, a substituted or unsubstituted alkyl group (preferably an unsubstituted alkyl group having 1 to 6 carbon atoms), a haloalkyl group (preferably a haloalkyl group having 1 to 6 carbon atoms), an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a haloalkoxy group (preferably a haloalkoxy group having 1 to 6 carbon atoms), a cyano group and the like, specifically, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a trifluoromethyl group, a trifluoromethoxy group, a methoxy group, an ethoxy group, a cyano group and the like. Among them, a fluorine atom, a methyl group and a trifluoromethoxy group are preferable.

Specific examples of the substituted or unsubstituted aryl group for R² include a phenyl group and a phenyl group substituted by preferable substituent(s) for the aforementioned aryl group, and the like.

Specific examples of the aromatic heterocyclic group for R² include a pyridyl group, a furyl group, a thienyl group, a pyrimidinyl group, a pyrazinyl group and the like. Among them, a pyridyl group and a furyl group are preferable.

R³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered cycloalkenyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, preferably a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, more preferably a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, or a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, still more preferably a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted 3- to 8-membered cycloalkyl group.

Preferable examples of the substituent for the alkyl group for R³ include a hydroxyl group, an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a O-5 to 8-membered saturated aliphatic heterocyclic group and the like, specifically, a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuryl group, a tetrahydropyranyl group and the like.

Preferable examples of the substituent for the saturated aliphatic heterocyclic group for R³ include an alkylcarbonyl group, an alkoxycarbonyl group, an alkylsulfonyl group, a mono-alkylcarbamoyl group (the alkyl moiety has preferably 1 to 6 carbon atoms) and the like, specifically, an acetyl group, a tert-butoxycarbonyl group, a methylsulfonyl group, an isopropylcarbamoyl group and the like.

Specific examples of R³ include an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methoxyethyl group, an ethoxyethyl group, an isopropoxyethyl group, a hydroxyethyl group, a methoxypropyl group, an ethoxypropyl group, a hydroxypropyl group, a tetrahydropyranyl group, a tetrahydrofuryl group, a 2,2-dimethyl-2-hydroxyethyl group, a tetrahydropyranylmethyl group, a tetrahydrofurylmethyl group, a 4-piperidyl group, a 1-(tert-butoxycarbonyl)piperidin-4-yl group, a 1-isopropylcarbamoylpiperidin-4-yl group, a 1-acetylpiperidin-4-yl group, a 1-methylsulfonylpiperidin-4-yl group and the like. R³ is more preferable a cyclobutyl group, a 2-ethoxyethyl group or an ethyl group.

R⁴ is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted 3- to 8-membered cycloalkyl group, preferably a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, more preferably a hydrogen atom.

Preferable examples of the substituent for the alkyl group and cycloalkyl group for R⁴ include a halogen atom, a hydroxyl group, an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a 4- to 8-membered saturated aliphatic heterocyclic group and the like, specifically, a fluorine atom, a chlorine atom, a hydroxyl group, a methoxy group, an ethoxy group, a tetrahydrofuryl group, a tetrahydropyranyl group and the like.

Specific examples of R⁴ include a hydrogen atom, a methyl group, cyclopropyl group and the like. Among them, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is more preferable.

R^(5a) and R^(5b) are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or R⁴ and R^(5a) are optionally bonded to form, together with the nitrogen atom that R⁴ is bonded to, a 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle (in this case, R^(5b) is a hydrogen atom), preferably independently each a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms. Preferable examples of the substituent for the alkyl group for R^(5a) or R^(5b) include a halogen atom, a hydroxyl group, an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a 4- to 8-membered saturated aliphatic heterocyclic group and the like, specifically, a fluorine atom, a chlorine atom, a hydroxyl group, a methoxy group, an ethoxy group, tetrahydrofuryl group, tetrahydropyranyl group and the like.

Specific examples of R^(5a) and R^(5b) include independently each a hydrogen atom, a methyl group, an ethyl group and an isopropyl group (preferably R^(5a) is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group, and R^(5b) is a methyl group, an ethyl group or an isopropyl group). Among them, a hydrogen atom and a methyl group are preferable (preferably R^(5a) is a hydrogen atom, and R^(5b) is a methyl group).

When R^(5a) and R^(5b) are different from each other, the carbon atom that they are bonded to is an asymmetric carbon atom, and the steric configuration is preferably S-configuration from the aspects of easy availability of the starting materials.

Specific examples of the 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle formed by R⁴ and R^(5a) which are bonded to each other, together with the nitrogen atom that R⁴ is bonded to, include an azetidine ring, a pyrrolidine ring, a piperidine ring and the like. Among them, pyrrolidine ring is preferable.

R⁶ and R⁷ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered cycloalkenyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group, or R⁶ and R⁷ are optionally bonded to form, together with the nitrogen atom that they are bond to, a substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle, or a substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocycle (the saturated or unsaturated nitrogen-containing aliphatic heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 3 nitrogen atoms), preferably independently each a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, more preferably independently each a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, more preferably a hydrogen atom.

Preferable examples of the substituent for the alkyl group for R⁶ or R⁷ include a hydroxyl group, an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a 4- to 8-membered saturated aliphatic heterocyclic group and the like, specifically, a hydroxyl group, a methoxy group, an ethoxy group, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, a piperidino group, a piperazinyl group, a morpholino group and the like. Specific examples of the substituted alkyl group for R⁶ or R⁷ include a methoxyethyl group, a 2,2-dimethyl-2-hydroxyethyl group, a morpholinoethyl group and the like.

Preferable specific examples of R⁶ or R⁷ include a hydrogen atom, a methyl group, an ethyl group, an isopropyl group and the like. Among them, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is more preferable.

Specific examples of the substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle and substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocycle, which are formed by R⁶ and R⁷ which are bonded to each other, together with the nitrogen atom that they are bond to, include a morpholine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring and the like. Among them, a morpholine ring and a piperazine ring are preferable.

Preferable examples of the substituent for the above-mentioned saturated nitrogen-containing aliphatic heterocycle and unsaturated nitrogen-containing aliphatic heterocycle include an oxo group, a cyano group, a haloalkyl group (preferably a haloalkyl group having 1 to 6 carbon atoms) and the like. Among them, an oxo group, a cyano group and a trifluoromethyl group are preferable.

Preferable examples of compound (1) include the following compounds and a pharmaceutically acceptable salt thereof.

Preferable embodiments thereof include a compound wherein

R¹ is a hydrogen atom or a halogen atom, L is a single bond or —O—, R² is a substituted or unsubstituted phenyl group, X is a carbon atom, R³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, R⁴ is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, R^(5a) and R^(5b) are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R⁶ and R⁷ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, or R⁶ and R⁷ are optionally bonded to form, together with the nitrogen atom that they are bond to, a substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle, or a substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocycle (the saturated or unsaturated nitrogen-containing aliphatic heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 3 nitrogen atoms).

Other preferable embodiments thereof include a compound wherein

R¹ is a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms, L is a single bond or —O—, R² is a substituted or unsubstituted 6- to 10-membered aryl group (the substituent is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms, more preferably a fluorine atom, a methyl group or a trifluoromethoxy group), X is a carbon atom, R³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (the substituent is preferably a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a 4- to 8-membered saturated aliphatic heterocyclic group, more preferably a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuryl group or a tetrahydropyranyl group), a substituted or unsubstituted 3- to 8-membered cycloalkyl group (preferably an unsubstituted 3- to 8-membered cycloalkyl group), a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group (preferably an unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group), or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group (preferably an unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group), R⁴ is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (preferably an unsubstituted alkyl group having 1 to 6 carbon atoms), R^(5a) and R^(5b) are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (preferably an unsubstituted alkyl group having 1 to 6 carbon atoms), and R⁶ and R⁷ are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (preferably an unsubstituted alkyl group having 1 to 6 carbon atoms).

Among them, a compound wherein

R¹ is a hydrogen atom or a halogen atom, L is a single bond or —O—, R² is a substituted or unsubstituted phenyl group (the substituent is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms, more preferably a fluorine atom, a methyl group or a trifluoromethoxy group), X is a carbon atom, R³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (the substituent is preferably a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a 4- to 8-membered saturated aliphatic heterocyclic group, more preferably a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuryl group or a tetrahydropyranyl group), or a substituted or unsubstituted 3- to 8-membered cycloalkyl group (preferably an unsubstituted 3- to 8-membered cycloalkyl group), R⁴ is a hydrogen atom or a methyl group, R^(5a) and R^(5b) are each independently a hydrogen atom, a methyl group, an ethyl group or an isopropyl group (preferably R^(5a) is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group, and R^(5b) is a methyl group, an ethyl group or an isopropyl group), and R⁶ and R⁷ is a hydrogen atom, is preferable, and a compound wherein R¹ is a hydrogen atom,

L is —O—,

R² is a substituted or unsubstituted phenyl group (the substituent is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms, more preferably a fluorine atom, a methyl group or a trifluoromethoxy group), X is a carbon atom, R³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (the substituent is preferably a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a 4- to 8-membered saturated aliphatic heterocyclic group, more preferably a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuryl group or a tetrahydropyranyl group), or a substituted or unsubstituted 3- to 8-membered cycloalkyl group (preferably an unsubstituted 3- to 8-membered cycloalkyl group), R⁴ is a hydrogen atom or a methyl group, R^(5a) and R^(5b) are each independently a hydrogen atom or a methyl group (preferably R^(5a) is a hydrogen atom, and R^(5b) is a methyl group), and R⁶ and R⁷ is a hydrogen atom, is more preferable.

The compound of the present invention is preferably compound (2) or compound (3) or a pharmaceutically acceptable salt thereof, more preferably compound (2) or a pharmaceutically acceptable salt thereof.

Preferable specific examples thereof include the following compounds and a pharmaceutically acceptable salt thereof.

Specific examples thereof include a compound wherein

R¹ is

(1) a hydrogen atom, (2) a halogen atom (preferably a fluorine atom, a chlorine atom), (3) a C₁₋₆ alkyl group (preferably methyl) or (4) a C₁₋₆ haloalkyl group (preferably trifluoromethyl),

L is

(1) a single bond,

(2) —O— or (3) —CH₂O—, R² is

(1) a C₆₋₁₀ aryl group (the C₆₋₁₀ aryl group is optionally condensed with a C₃₋₆ cycloalkane) (preferably phenyl, indanyl, more preferably phenyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (preferably a fluorine atom, a chlorine         atom),     -   (b) a C₁₋₆ alkyl group (preferably methyl, ethyl, isopropyl,         tert-butyl),     -   (c) a C₁₋₆ haloalkyl group (preferably trifluoromethyl),     -   (d) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy),     -   (e) a C₁₋₆ haloalkoxy group (preferably trifluoromethoxy) and     -   (f) a cyano group, or         (2) a 5- to 10-membered aromatic heterocyclic group (preferably         a 5- or 6-membered aromatic heterocyclic group, more preferably         pyridyl, furyl),         X is a carbon atom or a nitrogen atom,

R³ is

(1) a C₁₋₆ alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy,         isopropoxy),     -   (b) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably tetrahydropyranyl, tetrahydrofuryl), and     -   (c) a hydroxyl group,         (2) a C₃₋₈ cycloalkyl group (preferably cyclopropyl, cyclobutyl,         cyclopentyl), or         (3) a 4- to 8-membered saturated aliphatic heterocyclic group         preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably tetrahydropyranyl, piperidyl) optionally         substituted by 1 to 3 substituents selected from     -   (a) a C₁₋₆ alkyl-carbonyl group (preferably acetyl),     -   (b) a C₁₋₆ alkoxy-carbonyl group (preferably         tert-butoxycarbonyl),     -   (c) a C₁₋₆ alkylsulfonyl group (preferably methylsulfonyl), and     -   (d) a carbamoyl group optionally mono- or di-substituted by C₁₋₆         alkyl group(s) (preferably isopropyl),

R⁴ is

(1) a hydrogen atom, or (2) a C₁₋₆ alkyl group (preferably methyl), R^(5a) and R^(5b) are each independently (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group (preferably methyl, ethyl, isopropyl), or R⁴ and R^(5a) are optionally bonded to form, together with the nitrogen atom that R⁴ is bonded to, a 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle (preferably a 5- or 6-membered saturated nitrogen-containing aliphatic heterocycle, more preferably pyrrolidine) (in this case, R^(5b) is a hydrogen atom), and R⁶ and R⁷ are each independently (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group (preferably ethyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a hydroxyl group,     -   (b) a C₁₋₆ alkoxy group (preferably methoxy), and     -   (c) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably morpholinyl), or         R⁶ and R⁷ are optionally bonded to form, together with the         nitrogen atom that they are bond to, a 4- to 8-membered         saturated nitrogen-containing aliphatic heterocycle (preferably         a 5- or 6-membered saturated nitrogen-containing aliphatic         heterocycle, more preferably morpholine, piperazine) optionally         substituted by 1 to 3 substituents selected from     -   (a) an oxo group,     -   (b) a cyano group, and     -   (c) a C₁₋₆ haloalkyl group (preferably trifluoromethyl).

Preferable specific examples thereof include a compound herein

R¹ is

(1) a hydrogen atom, or (2) a halogen atom (preferably a fluorine atom, a chlorine atom),

L is

(1) a single bond, or

(2) —O—,

R² is a phenyl group optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (preferably a fluorine atom, a chlorine         atom),     -   (b) a C₁₋₆ alkyl group (preferably methyl, ethyl, isopropyl,         tert-butyl),     -   (c) a C₁₋₆ haloalkyl group (preferably trifluoromethyl),     -   (d) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy),     -   (e) a C₁₋₆ haloalkoxy group (preferably trifluoromethoxy), and     -   (f) a cyano group,         X is a carbon atom,

R³ is

(1) a C₁₋₆ alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy,         isopropoxy),     -   (b) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably tetrahydropyranyl, tetrahydrofuryl), and     -   (c) a hydroxyl group,         (2) a C₃₋₈ cycloalkyl group (preferably cyclopropyl, cyclobutyl,         cyclopentyl), or         (3) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably tetrahydropyranyl, piperidyl) optionally         substituted by 1 to 3 substituents selected from     -   (a) a C₁₋₆ alkyl-carbonyl group (preferably acetyl),     -   (b) a C₁₋₆ alkoxy-carbonyl group (preferably         tert-butoxycarbonyl),     -   (c) a C₁₋₆ alkylsulfonyl group (preferably methylsulfonyl), and     -   (d) a carbamoyl group optionally mono- or di-substituted by C₁₋₆         alkyl group(s) (preferably isopropyl),

R⁴ is

(1) a hydrogen atom, or (2) a C₁₋₆ alkyl group (preferably methyl), R^(5a) and R^(5b) are each independently (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group (preferably methyl, ethyl, isopropyl), and R⁶ and R⁷ are each independently (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group (preferably ethyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a hydroxyl group,     -   (b) a C₁₋₆ alkoxy group (preferably methoxy), and     -   (c) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably morpholinyl), or         R⁶ and R⁷ are optionally bonded to form, together with the         nitrogen atom that they are bond to, a 4- to 8-membered         saturated nitrogen-containing aliphatic heterocycle (preferably         a 5- or 6-membered saturated nitrogen-containing aliphatic         heterocycle, more preferably morpholine, piperazine) optionally         substituted by 1 to 3 substituents selected from     -   (a) an oxo group,     -   (b) a cyano group, and     -   (c) a C₁₋₆ haloalkyl group (preferably trifluoromethyl).

Other preferable specific examples thereof include a compound wherein

R¹ is

(1) a hydrogen atom, (2) a halogen atom (preferably a fluorine atom, a chlorine atom), or (3) a C₁₋₆ alkyl group (preferably methyl),

L is

(1) a single bond, or

(2) —O—,

R² is a C₆₋₁₀ aryl group (the C₆₋₁₀ aryl group is optionally condensed with a C₃₋₆ cycloalkane) (preferably phenyl, indanyl, more preferably phenyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (preferably a fluorine atom, a chlorine         atom),     -   (b) a C₁₋₆ alkyl group (preferably methyl, ethyl, isopropyl,         tert-butyl),     -   (c) a C₁₋₆ haloalkyl group (preferably trifluoromethyl),     -   (d) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy),     -   (e) a C₁₋₆ haloalkoxy group (preferably trifluoromethoxy), and     -   (f) a cyano group,         X is a carbon atom,

R³ is

(1) a C₁₋₆ alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy,         isopropoxy),     -   (b) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably tetrahydropyranyl, tetrahydrofuryl), and     -   (c) a hydroxyl group,         (2) a C₃₋₈ cycloalkyl group (preferably cyclopropyl, cyclobutyl,         cyclopentyl), or         (3) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably tetrahydropyranyl, piperidyl) optionally         substituted by 1 to 3 substituents selected from     -   (a) a C₁₋₆ alkyl-carbonyl group (preferably acetyl),     -   (b) a C₁₋₆ alkoxy-carbonyl group (preferably         tert-butoxycarbonyl),     -   (c) a C₁₋₆ alkylsulfonyl group (preferably methylsulfonyl), and     -   (d) a carbamoyl group optionally mono- or di-substituted by C₁₋₆         alkyl group(s) (preferably isopropyl),

R⁴ is

(1) a hydrogen atom, or (2) a C₁₋₆ alkyl group (preferably methyl), R^(5a) and R^(5b) are each independently (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group (preferably methyl, ethyl, isopropyl), and R⁶ and R⁷ are each independently (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group (preferably ethyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a hydroxyl group,     -   (b) a C₁₋₆ alkoxy group (preferably methoxy), and     -   (c) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably morpholinyl).

Among them, a compound wherein

R¹ is

(1) a hydrogen atom, or (2) a halogen atom (preferably a fluorine atom, a chlorine atom),

L is

(1) a single bond, or

(2) —O—,

R² is a phenyl group optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (preferably a fluorine atom, a chlorine         atom),     -   (b) a C₁₋₆ alkyl group (preferably methyl, ethyl, isopropyl,         tert-butyl),     -   (c) a C₁₋₆ haloalkyl group (preferably trifluoromethyl),     -   (d) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy),     -   (e) a C₁₋₆ haloalkoxy group (preferably trifluoromethoxy), and     -   (f) a cyano group,         X is a carbon atom,

R³ is

(1) a C₁₋₆ alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy,         isopropoxy),     -   (b) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably tetrahydropyranyl, tetrahydrofuryl), and     -   (c) a hydroxyl group, or         (2) a C₃₋₈ cycloalkyl group (preferably cyclopropyl, cyclobutyl,         cyclopentyl),         R⁴ is a hydrogen atom or a methyl group,         R^(5a) and R^(5b) are each independently a hydrogen atom, a         methyl group, an ethyl group or an isopropyl group (preferably         R^(5a) is a hydrogen atom, a methyl group, an ethyl group or an         isopropyl group, and R^(5b) is a methyl group, an ethyl group or         an isopropyl group), and         R⁶ and R⁷ is a hydrogen atom,         is preferable, and         a compound wherein         R¹ is a hydrogen atom,

L is —O—,

R² is a phenyl group optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (preferably a fluorine atom, a chlorine         atom),     -   (b) a C₁₋₆ alkyl group (preferably methyl, ethyl, isopropyl,         tert-butyl),     -   (c) a C₁₋₆ haloalkyl group (preferably trifluoromethyl),     -   (d) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy),     -   (e) a C₁₋₆ haloalkoxy group (preferably trifluoromethoxy), and     -   (f) a cyano group,         X is a carbon atom,

R³ is

(1) a C₁₋₆ alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

-   -   (a) a C₁₋₆ alkoxy group (preferably methoxy, ethoxy,         isopropoxy),     -   (b) a 4- to 8-membered saturated aliphatic heterocyclic group         (preferably a 5- or 6-membered saturated aliphatic heterocyclic         group, more preferably tetrahydropyranyl, tetrahydrofuryl), and     -   (c) a hydroxyl group, or         (2) a C₃₋₈ cycloalkyl group (preferably cyclopropyl, cyclobutyl,         cyclopentyl),         R⁴ is a hydrogen atom or a methyl group, and         R^(5a) and R^(5b) are each independently a hydrogen atom or a         methyl group (preferably R^(5a) is a hydrogen atom, and R^(5b)         is a methyl group), and         R⁶ and R⁷ is a hydrogen atom,         is more preferable.

Other preferable specific examples thereof include

-   N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}glycinamide, -   N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide, -   N²-{[1-cyclopropyl-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-cyclobutyl-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(4-chlorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(4-fluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(4-fluorophenoxy)-1-(3-methoxypropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(2-chloro-4-fluorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-(2-ethoxyethyl)-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-ethyl-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[1-(3-methoxypropyl)-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[6-(4-methylphenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, -   N²-{[5-chloro-1-(2-ethoxyethyl)-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,     and -   N²-{[5-chloro-6-(3,4-difluorophenyl)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,     and     pharmaceutically acceptable salts thereof.

Compound (1) can be prepared, for example, according to the method shown below.

wherein R¹, R², R³, R⁴, R^(5a), R^(5b), R⁶, R⁷, L and X are as defined above.

Compound (1) can be prepared by subjecting compound (1-1) to a reductive amination with the corresponding amine compound. As the solvent, ether solvents such as tetrahydrofuran, 1,4-dioxane and the like, halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethane and the like, alcohol solvents such as methanol, ethanol and the like, ethyl acetate, N,N-dimethylformamide, acetonitrile and the like can be used. Among them, tetrahydrofuran, dichloromethane and methanol are preferable. As the reducing agent, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like can be used. The reaction temperature is −20° C.—the refluxing temperature of the reaction solvent, and particularly preferably 0° C.—near room temperature. Molecular sieves or sodium sulfate may be added as a dehydrating agent. Acetic acid or hydrochloric acid may be added as an additive.

Compound (1A), which is compound (1) wherein R⁴ and R^(5a) are not bonded, can also be prepared from compound (1-1) according to the method shown in Reaction Scheme-2 below.

wherein R¹, R², R³, R⁴, R^(5a), R^(5b), R⁶, R⁷, L and X are as defined above except that R⁴ and R^(5a) are not bonded, and Y is a leaving group such as a halogen atom, a mesyloxy group, a tosyloxy group and the like.

Compound (1-1) is subjected to a reductive amination with compound (1-2) to give compound (1-3), and compound (1-3) is reacted with compound (1-4) in the presence of a base, in a solvent such as ether solvent (e.g., tetrahydrofuran, 1,4-dioxane and the like), halogenated solvent (e.g., dichloromethane, chloroform, 1,2-dichloroethane and the like), ethyl acetate, N,N-dimethylformamide, acetonitrile and the like, at 0° C.—the refluxing temperature of the reaction solvent to give compound (1A). While the base is not particularly limited, inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like, and organic bases such as triethylamine, diisopropylethylamine and the like can be used.

In addition, compound (1) can also be prepared according to the method shown in Reaction Scheme-3 below.

wherein R¹, R², R³, R⁴, R^(5a), R^(5b), R⁶, R⁷, L, Y and X are as defined above.

Compound (1) can be prepared by reacting compound (1-5) with the corresponding amine compound in the presence of a base, in a solvent such as ether solvent (e.g., tetrahydrofuran, 1,4-dioxane and the like), halogenated solvent (e.g., dichloromethane, chloroform, 1,2-dichloroethane and the like), ethyl acetate, N,N-dimethylformamide, acetonitrile and the like, at 0° C.—the refluxing temperature of the reaction solvent. While the base is not particularly limited, inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like, and organic bases such as triethylamine, diisopropylethylamine and the like can be used.

Compound (1B), which is compound (1) wherein R⁴ is a hydrogen atom, can be prepared, for example, by the method shown in Reaction Scheme-4 below.

wherein R¹, R², R³, R^(5a), R^(5b), R⁶, R⁷, L, Y and X are as defined above.

Compound (1B) can be prepared by reacting compound (1-7), which is obtained from compound (1-5) and compound (1-6) in the same manner as in Reaction Scheme-3, in an acidic solvent such as trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid and the like, at room temperature—the refluxing temperature of the reaction solvent. The reaction is more preferably performed in trifluoroacetic acid at around 50° C.

The above-mentioned compounds (1-1) and (1-5) can be prepared by the method shown below and a method analogous thereto.

Of the above-mentioned compound (1-1), compound (2-1) can be prepared, for example, by the method shown in Reaction Scheme-5 below.

wherein R² and R³ are as defined above.

Compound (2-3) can be prepared by reacting 2,4-Difluoronitrobenzene with compound (2-2) in the presence of a base, in a solvent such as ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1,4-dioxane and the like), N,N-dimethylformamide, acetonitrile and the like, at room temperature—the refluxing temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and potassium carbonate is preferably used. As the solvent, 1,4-dioxane is preferable.

Compound (2-5) can be prepared by reacting compound (2-3) with compound (2-4) in the presence of a base, in a solvent such as ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1,4-dioxane and the like), N,N-dimethylformamide, acetonitrile and the like, at room temperature—the refluxing temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and cesium carbonate is preferably used. As the solvent, 1,4-dioxane is preferable.

Compound (2-6) can be prepared by reducing the nitro group of compound (2-5) to an amino group. The reduction to be used in this reaction may be performed under conventional reduction conditions. Preferred are catalytic reduction by palladium-carbon and the like, reduction using a metal such as iron and the like, and the like. The solvent to be used for the reduction is preferably selected according to the reduction conditions. For example, for catalytic reduction, methanol, ethanol, tetrahydrofuran, ethyl acetate and the like are preferably selected and, for reduction using a metal such as iron and the like, tetrahydrofuran, acetic acid, methanol, ethanol, water and the like are selected. The catalytic reduction is preferably performed at room temperature, and the reduction using a metal such as iron and the like is preferably performed at 50° C.—the refluxing temperature of the reaction solvent.

Compound (2-1) can be prepared by mixing compound (2-6) with glycolic acid and heating them from 100° C. to 150° C., and by oxidizing the hydroxyl group of the obtained corresponding cyclic compound. The oxidation to be used for this reaction may be performed under conventional oxidation conditions. Examples thereof include oxidation with manganese dioxide, chrome and the like, and oxidation with organic oxidant represented by dimethyl sulfoxide. The oxidation with manganese dioxide and Swern oxidation are preferable. Of these, oxidation with manganese dioxide is particularly preferable. The solvent to be used for the oxidation is preferably selected according to the oxidation conditions. For example, for oxidation with a metal, halogenated solvents such as dichloromethane, chloroform and the like, and ether solvents such as tetrahydrofuran, dimethoxyethane, 1,4-dioxane and the like are preferably selected. For oxidation with an organic oxidant, halogenated solvents such as dichloromethane, chloroform and the like are preferable. The oxidation with metal is preferably performed at room temperature, and the oxidation with an organic oxidant is preferably performed at −78° C.—room temperature.

In the above-mentioned compound (1-1), compound (3-1) can also be prepared, for example, by the method shown in Reaction Scheme-6 below.

wherein R² and R³ are as defined above.

Compound (3-4) can be prepared by reacting compound (3-2) with compound (3-3) in the presence of a base, in a solvent such as ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1,4-dioxane and the like), N,N-dimethylformamide, acetonitrile and the like, at room temperature—the refluxing temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and potassium carbonate is preferably used. As the solvent, 1,4-dioxane is preferable.

Compound (3-5) can be prepared by reducing the nitro group of compound (3-4) to an amino group. The reduction to be used in this reaction is preferably a reduction using a metal such as iron, tin etc., and the like. A solvent to be used for the reduction is preferably tetrahydrofuran, acetic acid, methanol, ethanol, water and the like. The reduction using a metal is preferably performed at 50° C.—the refluxing temperature of the reaction solvent.

Compound (3-6) can be prepared by mixing compound (3-5) with glycolic acid and heating them from 100° C. to 150° C. Compound (3-7) can be prepared by oxidizing the hydroxyl group of compound (3-6). The oxidation to be used for this reaction may be performed under conventional oxidation conditions. Examples thereof include oxidation with manganese dioxide, chrome and the like, and oxidation with an organic oxidant represented by dimethyl sulfoxide. The oxidation with manganese dioxide and Swern oxidation are preferable. Of these, oxidation with manganese dioxide is particularly preferable. The solvent to be used for the oxidation is preferably selected according to the oxidation conditions. For example, for oxidation with a metal, halogenated solvent such as dichloromethane, chloroform and the like, ether solvent such as tetrahydrofuran, dimethoxyethane, 1,4-dioxane and the like are preferable and, for oxidation with an organic oxidant, halogenated solvent such as dichloromethane, chloroform and the like are preferable. The oxidation with a metal is preferably performed at room temperature, and the oxidation with an organic oxidant is preferably performed at −78° C. to room temperature.

Compound (3-1) can be prepared by reacting compound (3-7) with the corresponding boranic acid compound by using a palladium catalyst, a ligand and a base, in a solvent such as dimethoxyethane, 1,4-dioxane, toluene, ethanol and the like, at room temperature—the refluxing temperature of the solvent. Examples of the palladium catalyst include, but are not particularly limited to, palladium acetate, tetrakistriphenylphosphine palladium, trisbenzylideneacetone dipalladium and the like. While the ligand is not particularly limited, examples thereof include triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine and the like. While the base is not particularly limited, examples thereof include sodium carbonate, potassium carbonate, cesium carbonate and the like.

In the above-mentioned compound (1-1), compound (4-1) can be prepared, for example, according to the method shown in Reaction Scheme-7 below.

wherein R² and R³ are as defined above.

Compound (4-3) can be prepared by reacting compound (3-6) with compound (4-2) by using a copper catalyst, a ligand and a base, in a solvent such as N-methylpyrrolidinone, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide and the like, at room temperature—the refluxing temperature of the solvent. While the copper catalyst is not particularly limited, examples thereof include copper iodide, copper bromide, copper chloride and the like. While the ligand is not particularly limited, examples thereof include 2,2,6,6-tetramethylheptane-3,5-dione, N,N-dimethylglycine and the like. While the base is not particularly limited, examples thereof include sodium carbonate, potassium carbonate, cesium carbonate and the like.

Compound (4-1) can be prepared by oxidizing the hydroxyl group of compound (4-3). The oxidation to be used for this reaction may be performed under conventional oxidation conditions. Examples thereof include oxidation with manganese dioxide, chrome and the like, and oxidation with organic oxidant represented by dimethyl sulfoxide. The oxidation with manganese dioxide and Swern oxidation are preferable. Of these, oxidation with manganese dioxide is particularly preferable.

The solvent to be used for the oxidation is preferably selected according to the oxidation conditions. For example, for oxidation with a metal, halogenated solvents such as dichloromethane, chloroform and the like, and ether solvents such as tetrahydrofuran, dimethoxyethane, 1,4-dioxane and the like are preferably selected. For oxidation with an organic oxidant, halogenated solvents such as dichloromethane, chloroform and the like are preferable. The oxidation with metal is preferably performed at room temperature, and the oxidation with an organic oxidant is preferably performed at −78° C.—room temperature.

In the above-mentioned compound (1-1), compound (5-1) can be prepared, for example, by the method shown in Reaction Scheme-8 below.

wherein R², R³ and Y are as defined above.

Compound (5-4) can be prepared by reacting compound (5-2) with compound (5-3) in the presence of a base, in a solvent such as ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1,4-dioxane and the like), N,N-dimethylformamide and the like, at room temperature—the refluxing temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and potassium carbonate is preferably used. As the solvent, N,N-dimethylformamide is preferable.

Compound (5-1) can be obtained from compound (5-4) in the same manner as in Reaction Scheme-5.

In the above-mentioned compound (1-1), compound (6-1) can be prepared, for example, according to Reaction Scheme-9 below.

wherein R² and R³ are as defined above.

Compound (6-3) can be prepared by reacting 2,6-Dichloro-3-nitropyridine with compound (6-2) in the presence of a base, in a solvent such as ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1,4-dioxane and the like), N,N-dimethylformamide, acetonitrile and the like, at room temperature—the refluxing temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and potassium carbonate is preferably used. As the solvent, 1,4-dioxane is preferable.

Compound (6-5) can be prepared by reacting compound (6-3) with compound (6-4) in the presence of a base, in a solvent such as ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1,4-dioxane and the like), N,N-dimethylformamide, acetonitrile and the like, at room temperature—the refluxing temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and cesium carbonate is preferably used. As the solvent, 1,4-dioxane is preferable.

Compound (6-1) can be obtained from compound (6-5) in the same manner as in Reaction Scheme-5.

In the above-mentioned compound (1-1), compound (7-1) can be prepared, for example, by the method shown in Reaction Scheme-10 below.

wherein R² and R³ are as defined above.

Compound (7-2) can be obtained from compound (6-3) in the same manner as in Reaction Scheme-6.

Compound (7-1) can be prepared by reacting compound (7-2) with the corresponding boranic acid compound by using a palladium catalyst, a ligand and a base, in a solvent such as dimethoxyethane, 1,4-dioxane, toluene, ethanol and the like, at room temperature—the refluxing temperature of the solvent. Examples of the palladium catalyst include, but are not particularly limited to, palladium acetate, tetrakistriphenylphosphine palladium, trisbenzylideneacetone dipalladium and the like. While the ligand is not particularly limited, examples thereof include triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine and the like. While the base is not particularly limited, examples thereof include sodium carbonate, potassium carbonate, cesium carbonate and the like.

The above-mentioned compound (1-5) can be prepared from compound (8-1), for example, by the method shown in Reaction Scheme-11 below.

wherein R¹, R², R³, L, X and Y are as defined above.

As a conversion step to a leaving group, when the leaving group Y is a mesyloxy group or a tosyloxy group, corresponding chloride (mesyl chloride, tosyl chloride) is reacted in the presence of a base such as triethylamine, pyridine and the like to give corresponding mesyl or tosyl form. When the leaving group Y is a halogen atom, the methods described in Comprehensive Organic Transformation [R. C. Larock, VCH Publishers Inc. (1989)], 4th Edition Jikken Kagaku Kouza (Maruzen), Shinjikken Kagaku Koza (Courses in Experimental Chemistry) (Maruzen) and the like can be employed. For example, corresponding bromide can be obtained by adding phosphorus tribromide in tetrahydrofuran.

Each of the aforementioned reactions can be performed according to the methods described in the Examples of the present specification, Comprehensive Organic Transformation [R. C. Larock, VCH Publishers Inc. (1989)], 4th Edition Jikken Kagaku Kouza (Maruzen), Shinjikken Kagaku Koza (Courses in Experimental Chemistry) (Maruzen).

In addition, the starting material compounds to be used in the aforementioned production methods can be appropriately prepared by using a commercially available product or according to a method known to those of ordinary skill in the art.

Furthermore, when the compound of the present invention or a pharmaceutically acceptable salt thereof is prepared, a functional group such as a hydroxyl group, a carboxyl group, an amino group and the like can be protected or deprotected in any step where necessary. The kind of the protecting group and the method of protection and deprotection may be those well known to those of ordinary skill in the art. For example, “Protective Groups in Organic Synthesis (T. W. Greene et al., John Wiley & Sons, Inc. published in 1991)” and the like may be referred to.

When compound (1) has a group capable of forming a salt in the structure, it can be converted as necessary to an acid addition salt with inorganic acid or organic acid, or an alkali addition salt, which is acceptable as a medicament. Examples of the pharmaceutically acceptable acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like, salts with organic carboxylic acid such as formate, acetate, fumarate, maleate, oxalate, citrate, malate, tartrate, aspartate, glutamate and the like, salts with sulfonic acid such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydroxybenzenesulfonate, dihydroxybenzenesulfonate and the like, and examples of the pharmaceutically acceptable alkali addition salt include ammonium salt, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt and the like.

In addition, the present invention also encompasses a hydrate, and a solvate such as ethanolate and the like, of compound (1) or a pharmaceutically acceptable salt thereof. Furthermore, the present invention encompasses any tautomer and stereoisomer such as optical isomer and the like, and any crystalline form, of compound (1). These can be appropriately purified by a method well known to those of ordinary skill in the art, such as silica gel column chromatography, HPLC, ion exchange chromatography, recrystallization and the like.

To obtain the aforementioned optical isomer in a pure form, an optical resolution method known to those of ordinary skill in the art may be used. To be specific, when the compound of the present invention or an intermediate thereof has a basic functional group, it can form a salt with an optically active acid (e.g., monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid and the like, dicarboxylic acids such as tartaric acid, o-diisopropylidenetartaric acid, malic acid and the like, sulfonic acids such as camphorsulfonic acid, bromocamphorsulfonic acid and the like) in an inert solvent. In addition, when the compound of the present invention or an intermediate thereof has an acidic functional group, it can also form a salt with optically active amine (e.g., organic amines such as α-phenethylamine, kinin, quinidine, cinchonidine, cinchonine, strychnine and the like). The temperature for the formation of the salt is from room temperature to the boiling point of the solvent.

The novel compound having a bicyclic heterocycle of the present invention or a pharmaceutically acceptable salt thereof has an SNS inhibitory activity and can be used as a therapeutic or prophylactic drug for neuropathic pain and nociceptive pain. Examples of the neuropathic pain here include neuralgia after lumbar operation, diabetic neuropathy, neuralgia after herpes zoster, reflex sympathetic dystrophy, phantom limb pain, spinal cord injury, late stage carcinomatous pain and prolonged postoperative pain. Examples of the nociceptive pain include lumbago, abdominal pain, rheumatoid arthritis, pain due to osteoarthritis and the like. In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof can also be used as a therapeutic or prophylactic drug for dysuria. Examples of the dysuria here include frequent urination, cystalgia due to benign prostatic hyperplasia and the like. Furthermore, it can also be used as a therapeutic or prophylactic drug for suppressing abnormal nervous firing in the cerebellum in multiple sclerosis. As a medicament free of side effects derived from normeural tissue or central nervous system, a compound having an SNS-selective inhibitory activity is more preferable.

The therapeutic or prophylactic drug of the present invention for neuropathic pain, nociceptive pain, dysuria or multiple sclerosis can contain various additional components for preparation such as conventional carrier, binder, stabilizer, excipient, diluent, pH buffering agent, disintegrant, solubilizer, dissolution aid, isotonic agent and the like, which are pharmaceutically acceptable. In addition, these therapeutic or prophylactic drugs can be orally or parenterally administered. That is, for oral administration, the drug can be orally administered in the form generally employed, for example, in dosage forms such as tablet, pill, powder, granule, capsule, syrup, emulsion, suspension and the like. For parenteral administration, the drug can be formulated as a preparation in the form of, for example, intravenous injection (drip infusion), intramuscular injection, subcutaneous injection, embrocation, eye drop, ophthalmic ointment and the like.

A solid preparation such as tablet is prepared by mixing the active ingredient with generally pharmacologically acceptable carrier or excipient such as lactose, sucrose, cornstarch and the like, binder such as crystalline cellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like, disintegrant such as carboxymethylcellulose sodium, starch sodium glycolate and the like, lubricant such as stearic acid, magnesium stearate and the like, preservative and the like.

For parenteral administration, the active ingredient may be dissolved or suspended in physiologically acceptable carrier such as water, saline, oil, aqueous glucose solution and the like, and may be added with emulsifier, stabilizer, salt for adjusting osmotic pressure or buffering agent as aids, where necessary.

The preparation of the compound of the present invention can be prepared according to a conventional method. For example, a tablet can be prepared by mixing the compound of Example 1 (20 mg), lactose (100 mg), crystalline cellulose (25 mg) and magnesium stearate (1 mg), and tableting the obtained mixture.

While the dose and frequency of administration vary depending on the administration method, and age, body weight, the disease state and the like of patients, a method of topical administration to a disease-injury lesion part is preferable. It is also preferable to administer the drug once or twice or more per day. When administering twice or more, consecutive administration or repeat administration at suitable intervals is desirable.

The dose is 10 μg-2 g, preferably 1 mg-1 g, more preferably 10-100 mg, in the amount of the active ingredient for an adult patient per single administration, which can be administered at once or in several portions a day. For parenteral administration, the dose can be 0.1-100 mg/day, more preferably 0.3-50 mg/day, for an adult patient, which can be administered at once or in several portions a day. To reduce administration frequency, a sustained-release preparation can also be used.

In addition, the therapeutic or prophylactic drug of the present invention for neuropathic pain, nociceptive pain, dysuria or multiple sclerosis can also be utilized as an animal drug.

EXAMPLES

The present invention is explained in more detail in the following by referring to Reference Examples and Examples; however, the technical scope of the present invention is not limited to such Examples and the like. The compounds were identified by hydrogen nuclear magnetic resonance absorption spectrum (¹H-NMR) and the like.

In the following, abbreviations shown below may be used sometimes to simplify the description of the present specification.

Me: methyl, Et: ethyl, Pr: propyl, iPr: isopropyl, Ph: phenyl, Ac: acetyl, Boc: tert-butoxycarbonyl, Bn: benzyl, TBDMS: tert-butyldimethylsilyl, PyBOP: benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate, J: binding constant, s: singlet, d: doublet, dd: double doublet, ddd: 4 doublets, td: 3 doublets, t: triplet, dt: double triplet, q: quartet, quint: quintet, br: broad, m: multiplet.

Unless otherwise specified, the starting material compounds, reaction reagents and solvents used were commercially available products.

Reference Example 1

To a solution of 2,4-difluoronitrobenzene (15 g, 94 mmol) in dioxane (300 mL) were added potassium carbonate (14.4 g, 104 mmol) and 2-ethoxyethylamine (8.4 g, 104 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the object product (21 g, 98%).

¹H-NMR (CDCl₃) δ 1.25 (t, J=7.1 Hz, 3H), 3.43 (q, J=5.2 Hz, 2H), 3.58 (q, J=7.1 Hz, 2H), 3.72 (t, J=5.2 Hz, 2H), 6.37 (ddd, J=9.5, 7.3, 2.5 Hz, 1H), 6.51 (dd, J=11.5, 2.5 Hz, 1H), 8.22 (dd, J=9.5, 6.1 Hz, 1H), 8.38 (br, 1H).

Reference Example 2

To a solution (60 mL) of the compound (3.0 g, 13.2 mmol) obtained in Reference Example 1 in dioxane were added cesium carbonate (6.4 g, 19.7 mmol) and phenol (1.5 g, 15.8 mmol), and the mixture was heated to 80° C. After stirring for 7 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the object product (4.1 g, 100%).

¹H-NMR (CDCl₃) δ 1.23 (t, J=7.0 Hz, 3H), 3.34 (q, J=5.2 Hz, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.67 (t, J=5.2 Hz, 2H), 6.22 (dd, J=9.4, 2.5 Hz, 1H), 6.29 (d, J=2.5 Hz, 1H), 7.07-7.12 (m, 2H), 7.23 (m, 1H), 7.35-7.45 (m, 2H), 8.16 (d, J=9.4 Hz, 1H), 8.39 (br, 1H).

Reference Example 3-1

To a solution (50 mL) of the compound (1.8 g, 6.0 mmol) obtained in Reference Example 2 in ethanol was added 10% palladium-carbon (1 g), and the mixture was stirred at room temperature for 4 hr under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated and dried under reduced pressure to give the object product (1.4 g, 86%).

¹H-NMR (CDCl₃) δ 1.22 (t, J=7.0 Hz, 3H), 3.21 (t, J=5.2 Hz, 2H), 3.23 (br, 2H), 3.53 (q, J=7.0 Hz, 2H), 3.67 (t, J=5.2 Hz, 2H), 6.34 (dd, J=8.3, 2.6 Hz, 1H), 6.40 (d, J=2.6 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 6.92-7.04 (m, 3H), 7.24-7.30 (m, 2H).

Reference Example 3-2

The above-mentioned object product can also be prepared by the following method.

To a suspension (3:2:1, 120 mL) of iron (13.9 g, 0.25 mol) and ammonium chloride (6.6 g, 0.12 mol) in tetrahydrofuran-methanol-water was added dropwise a solution (60 mL) of the compound (9.8 g, 32 mmol) obtained in Reference Example 2 in a mixed solvent (3:2:1) of tetrahydrofuran-methanol-water while refluxing under heating. After stirring for 2 hr, the reaction mixture was allowed to cool, and filtered through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the object product (8.7 g, 100%).

Reference Example 4

To the compound (5.0 g, 18.4 mmol) obtained in Reference

Example 3 was added glycolic acid (8 g), and the mixture was stirred at 120° C. for 30 min. After cooling, water and chloroform were added to the reaction mixture, and the mixture was neutralized with 30% aqueous sodium hydroxide solution under ice-cooling. The organic layer was extracted, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform:methanol=50:1-30:1) to give the object crude product (4.1 g).

Reference Example 5

To a solution of the compound (4.1 g) obtained in Reference Example 4 in dichloromethane (100 mL) was added manganese dioxide (8 g), and the mixture was stirred at room temperature. After stirring for 2 hr, the reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column (ethyl acetate:hexane=1:2) to give the object product (3.5 g, 61%, 2 steps).

¹H-NMR (CDCl₃) δ 1.03 (t, J=7.0 Hz, 3H), 3.37 (q, J=7.0 Hz, 2H), 3.73 (t, J=5.3 Hz, 2H), 4.66 (t, J=5.3 Hz, 2H), 7.04-7.20 (m, 5H), 7.34-7.41 (m, 2H), 7.86 (d, J=8.8 Hz, 1H), 10.05 (s, 1H).

Reference Example 6

The object crude product obtained from 2,4-difluoronitrobenzene (20.0 g, 126 mmol) and 4-fluorophenol in the same manner as in Reference Examples 1-4 was recrystallized from chloroform/hexane and further recrystallized from acetonitrile to give the object product (23.3 g, 56%, 4 steps).

¹H-NMR (CDCl₃) δ 1.05 (t, J=7.0 Hz, 3H), 3.37 (q, J=7.0 Hz, 2H), 3.70 (t, J=5.1 Hz, 2H), 4.34 (t, J=5.1 Hz, 2H), 4.89 (s, 2H), 6.89-7.03 (m, 6H), 7.58 (m, 1H).

Reference Example 7

The object product was obtained in the same manner as in Reference Example 5 from the compound obtained in Reference Example 6.

¹H-NMR (CDCl₃) δ 0.99 (t, J=7.0 Hz, 3H), 3.33 (q, J=7.0 Hz, 2H), 3.69 (t, J=5.1 Hz, 2H), 4.62 (t, J=5.1 Hz, 2H), 6.92-7.09 (m, 6H), 7.81 (m, 1H), 10.00 (s, 1H).

Example 1 N²-{[1-(2-ethoxyethyl)-6-phenoxy-1H-benzimidazol-2-yl]methyl}-L-alaninamide

To a solution of the compound (2.0 g, 6.5 mmol) obtained in Reference Example 5 in dichloromethane (50 mL) was added (L)-alaninamide hydrochloride (0.96 g, 7.7 mmol), and the mixture was stirred at room temperature. After stirring for 1 hr, sodium triacetoxyborohydride (1.6 g, 7.7 mmol) was added thereto, and the mixture was stirred for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform:methanol=50:1-10:1) to give the object product (0.59 g, 24%).

¹H-NMR (CDCl₃) δ 1.08 (t, J=7.1 Hz, 3H), 1.41 (d, J=7.0 Hz, 3H), 3.33 (q, J=7.0 Hz, 1H), 3.38 (q, J=7.1 Hz, 2H), 3.68 (t, J=5.1 Hz, 2H), 4.04 (d, J=14.7 Hz, 1H), 4.12 (d, J=14.7 Hz, 1H), 4.17-4.32 (m, 2H), 5.50 (brs, 1H), 6.98-7.02 (m, 4H), 7.09 (m, 1H), 7.28-7.36 (m, 3H), 7.68 (m, 1H).

The above-mentioned compound can also be prepared by the following method.

To a solution of the compound (0.15 g, 0.48 mmol) obtained in Reference Example 5 in tetrahydrofuran (10 mL) were added (L)-alaninamide hydrochloride (0.18 g, 1.45 mmol), sodium sulfate (3 g) and triethylamine (0.20 mL), and the mixture was stirred at room temperature. After stirring for 30 min, sodium cyanoborohydride (45 mg, 0.72 mmol) was added thereto, and the mixture was stirred for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was extracted, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform:methanol=50:1-10:1) to give the object product (0.09 g, 49%).

Example 2 N²-{[1-(2-ethoxyethyl)-6-phenoxy-1H-benzimidazol-2-yl]methyl}glycinamide

To a solution of the compound (44 mg, 0.14 mmol) obtained in Reference Example 5 in methanol (3 mL) was added glycinamide hydrochloride (31 mg, 0.28 mmol), and the mixture was stirred at room temperature. After stirring for 1 hr, sodium cyanoborohydride (18 mg, 0.28 mmol) was added thereto, and the mixture was stirred overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform:methanol=50:1-10:1) to give the object product (23 mg, 43%).

¹H-NMR (CDCl₃) δ 1.08 (t, J=7.0 Hz, 3H), 3.38 (q, J=7.0 Hz, 2H), 3.42 (s, 2H), 3.68 (t, J=5.1 Hz, 2H), 4.10 (s, 2H), 4.26 (t, J=5.1 Hz, 2H), 5.72 (brs, 1H), 6.96-7.02 (m, 4H), 7.08 (m, 1H), 7.21 (brs, 1H), 7.28-7.36 (m, 2H), 7.68 (m, 1H).

Example 3 N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}glycinamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 7.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 3.39 (q, J=7.0 Hz, 2H), 3.42 (s, 2H), 3.69 (t, J=5.0 Hz, 2H), 4.10 (s, 2H), 4.26 (t, J=5.0 Hz, 2H), 5.54 (brs, 1H), 6.93-7.05 (m, 6H), 7.18 (brs, 1H), 7.67 (m, 1H).

Example 4 N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-valinamide

The object product was obtained in the same manner as in Example 1 from the compound obtained in Reference Example 7 and (L)-valinamide hydrochloride.

¹H-NMR (CDCl₃) δ 0.99 (d, J=7.0 Hz, 3H), 1.02 (d, J=7.0 Hz, 3H), 1.08 (t, J=7.0 Hz, 3H), 2.08 (m, 1H), 2.97 (d, J=5.5 Hz, 1H), 3.38 (q, J=7.0 Hz, 2H), 3.68 (t, J=5.1 Hz, 2H), 3.98 (d, J=14.5 Hz, 1H), 4.15 (d, J=14.5 Hz, 1H), 4.17-4.40 (m, 2H), 5.56 (brs, 1H), 6.93-7.01 (m, 7H), 7.67 (m, 1H).

Example 5 N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide

The object product was obtained in the same manner as in Example 1 from the compound obtained in Reference Example 7 and 2-methylalaninamide which is a known compound.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.46 (s, 6H), 3.38 (q, J=7.0 Hz, 2H), 3.69 (t, J=5.1 Hz, 2H), 4.02 (s, 2H), 4.24 (t, J=5.1 Hz, 2H), 5.43 (brs, 1H), 6.93-7.05 (m, 6H), 7.48 (brs, 1H), 7.68 (m, 1H).

Examples 6-58

The compounds of Examples 6-58 shown in Table 1-Table 9 were prepared in the same manner as in Reference Examples 1-7, Example 1 or Example 2 from 2,4-difluoronitrobenzene and using commercially available or known compounds.

TABLE 1 Example structural formula ¹H-NMR (CDCl₃) δ  6

1.40 (d, J = 7.0 Hz, 3H), 1.79-1.88 (m, 2H), 2.42- 2.58 (m, 2H), 3.28 (q, J = 7.0 Hz, 1H), 3.51- 3.58 (m, 2H), 4.03 (d, J = 14.8 Hz, 1H), 4.11 (d, J = 14.8 Hz, 1H), 4.13-4.19 (m, 2H), 4.48 (m, 1H), 5.45 (brs, 1H), 6.91-7.05 (m, 6H), 7.26 (brs, 1H), 7.67 (d, J = 8.8 Hz, 1H).  7

0.98-1.05 (m, 2H), 1.15- 1.27 (m, 2H), 1.44 (d, J = 7.0 Hz, 3H), 3.18 (m, 1H), 3.35 (q, J = 7.0 Hz, 1H), 4.09 (d, J = 15.6 Hz, 1H), 4.17 (d, J = 15.6 Hz, 1H), 5.35 (brs, 1H), 6.91-7.05 (m, 5H), 7.14 (d, J = 2.4 Hz, 1H), 7.25 (brs, 1H), 7.63 (d, J = 8.8 Hz, 1H).  8

1.47 (s, 6H), 1.80-1.86 (m, 2H), 2.44-2.58 (m, 2H), 3.50-3.59 (m, 2H), 4.01 (s, 2H), 4.14-4.19 (m, 2H), 4.43 (m, 1H), 5.84 (brs, 1H), 6.90-7.04 (m, 5H), 7.16 (brs, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H).  9

1.40 (d, J = 7.0 Hz, 3H), 1.58 (d, J = 7.0 Hz, 6H), 3.30 (q, J = 7.0 Hz, 1H), 4.01 (d, J = 14.7 Hz, 1H), 4.08 (d, J = 14.7 Hz, 1H), 4.69 (m, 1H), 6.10 (brs, 1H), 6.92-7.02 (m, 3H), 7.07 (m, 1H), 7.15 (brs, 1H), 7.21 (m, 1H), 7.27-7.37 (m, 2H), 7.65 (d, J = 8.6 Hz, 1H). 10

1.58 (d, J = 7.0 Hz, 6H), 3.43 (s, 2H), 4.07 (s, 2H), 4.69 (m, 1H), 6.15 (brs, 1H), 6.91-7.01 (m, 4H), 7.04 (m, 1H), 7.11 (brs, 1H), 7.20 (d, J = 1.9 Hz, 1H), 7.29-7.36 (m, 2H), 7.64 (d, J = 8.8 Hz, 1H). 11

1.42 (d, J = 7.0 Hz, 3H), 1.82- 2.04 (m, 2H), 2.44-2.58 (m, 2H), 2.76-2.91 (m, 2H), 3.30 (q, J = 7.0 Hz, 1H), 3.99 (d, J = 14.1 Hz, 1H), 4.06 (d, J = 14.1 Hz, 1H), 4.87 (m, 1H), 5.52 (brs, 1H), 6.94-7.11 (m, 4H), 7.13 (brs, 1H), 7.30-7.37 (m, 3H), 7.66 (d, J = 8.8 Hz, 1H).

TABLE 2 Example structural formula ¹H-NMR (CDCl₃) δ 12

1.88-2.04 (m, 2H), 2.46-2.59 (m, 2H), 2.76-2.92 (m, 2H), 3.44 (s, 2H), 4.05 (s, 2H), 4.88 (m, 1H), 5.50 (brs, 1H), 6.95-7.12 (m, 5H), 7.30-7.36 (m, 3H), 7.66 (d, J = 8.8 Hz, 1H). 13

1.30-1.54 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H), 2.06 (m, 1H), 3.22-3.37 (m, 3H), 3.86-4.10 (m, 6H), 5.51 (brs, 1H), 6.96-7.13 (m, 6H), 7.29-7.35 (m, 2H), 7.67 (m, 1H). 14

1.32-1.54 (m, 4H), 2.06 (m, 1H), 3.30 (td, J = 11.5, 2.6 Hz, 2H), 3.45 (s, 2H), 3.92-4.00 (m, 4H), 4.06 (s, 2H), 5.57 (brs, 1H), 6.96- 7.12 (m, 6H), 7.30-7.37 (m, 2H), 7.67 (m, 1H). 15

1.08 (t, J = 7.0 Hz, 3H), 1.78-2.05 (m, 3H), 2.29 (m, 1H), 2.60 (m, 1H), 3.16 (m, 1H), 3.28-3.42 (m, 3H), 3.70 (t, J = 5.2 Hz, 2H), 3.94 (d, J = 14.3 Hz, 1H), 4.21 (d, J = 14.3 Hz, 1H), 4.27-4.38 (m, 2H), 5.39 (brs, 1H), 6.93- 7.06 (m, 6H), 7.64 (brs, 1H), 7.68 (d, J = 9.4 Hz, 1H). 16

1.32-1.52 (m, 4H), 1.80-2.35 (m, 5H), 2.59 (q, J = 8.4 Hz, 1H), 3.20-3.36 (m, 4H), 3.88-4.18 (m, 6H), 5.50 (brs, 1H), 6.96-7.12 (m, 5H), 7.28-7.38 (m, 2H), 7.44 (brs, 1H), 7.68 (m, 1H). 17

1.42 (d, J = 6.8 Hz, 3H), 1.86- 2.04 (m, 2H), 2.47-2.57 (m, 2H), 2.78-2.88 (m, 2H), 3.30 (q, J = 6.8 Hz, 1H), 3.99 (d, J = 15.0 Hz, 1H), 4.06 (d, J = 15.0 Hz, 1H), 4.87 (m, 1H), 5.45 (brs, 1H), 6.90-7.06 (m, 5H), 7.12 (brs, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H).

TABLE 3 Example structural formula ¹H-NMR (CDCl₃) δ 18

1.86-2.06 (m, 2H), 2.30-2.58 (m, 2H), 2.75-2.90 (m, 2H), 3.43 (s, 2H), 4.05 (s, 2H), 4.87 (m, 1H), 5.59 (brs, 1H), 6.90-7.10 (m, 6H), 7.27 (m, 1H), 7.65 (d, J = 8.8 Hz, 1H). 19

1.56 (m, 1H), 1.80-2.06 (m, 6H), 2.29 (m, 1H), 2.58 (q, J = 8.5 Hz, 1H), 3.18 (m, 1H), 3.32 (dd, J = 9.8, 5.4 Hz, 1H), 3.67-3.82 (m, 2H), 3.95 (d, J = 14.4 Hz, 1H), 4.11- 4.34 (m, 4H), 5.28 (brs, 1H), 6.96-7.10 (m, 5H), 7.29-7.35 (m, 2H), 7.67 (brs, 1H), 7.68 (d, J = 8.5 Hz, 1H). 20

1.41 (d, J = 7.1 Hz, 3H), 1.55 (m, 1H), 1.80-1.93 (m, 2H), 2.10 (m, 1H), 3.35 (q, J = 7.1 Hz, 1H), 3.67-3.83 (m, 2H), 4.00-4.30 (m, 5H), 5.41 (brs, 1H), 6.85-7.10 (m, 5H), 7.25-7.35 (m, 3H), 7.67 (d, J = 8.5 Hz, 1H). 21

1.55 (m, 1H), 1.80-2.08 (m, 6H), 2.28 (m, 1H), 2.61 (q, J = 8.6 Hz, 1H), 3.22 (m, 1H), 3.33 (dd, J = 9.7, 5.4 Hz, 1H), 3.67-3.81 (m, 2H), 3.98 (d, J = 14.6 Hz, 1H), 4.15- 4.24 (m, 4H), 5.33 (brs, 1H), 6.96-7.10 (m, 5H), 7.29-7.35 (m, 2H), 7.55 (brs, 1H), 7.68 (d, J = 8.5 Hz, 1H). 22

1.41 (d, J = 6.8 Hz, 3H), 1.56 (m, 1H), 1.85-1.95 (m, 2H), 2.05 (m, 1H), 3.32 (q, J = 6.8 Hz, 1H), 3.67-3.84 (m, 2H), 4.03-4.22 (m, 5H), 5.36 (brs, 1H), 6.80-7.10 (m, 5H), 7.24- 7.34 (m, 3H), 7.67 (d, J = 8.5 Hz, 1H). 23

2.02 (m, 2H), 3.27-3.34 (m, 5H), 3.45 (s, 2H), 4.07 (s, 2H), 4.21 (t, J = 6.8 Hz, 2H), 5.78 (brs, 1H), 6.98-7.10 (m, 5H), 7.21 (brs, 1H), 7.30- 7.35 (m, 2H), 7.67 (m, 1H).

TABLE 4 Example structural formula ¹H-NMR (CDCl₃) δ 24

1.42 (d, J = 6.8 Hz, 3H), 2.00-2.26 (m, 2H), 3.28 (s, 3H), 3.28-3.36 (m, 3H), 4.01 (d, J = 14.5 Hz, 1H), 4.07 (d, J = 14.5 Hz, 1H), 4.28 (t, J = 6.8 Hz, 2H), 5.47 (brs, 1H), 6.97-7.10 (m, 5H), 7.23 (brs, 1H), 7.29- 7.34 (m, 2H), 7.67 (m, 1H). 25

1.74-2.38 (m, 8H), 3.44 (s, 2H), 4.09 (s, 2H), 4.78 (m, 1H), 5.93 (brs, 1H), 6.93- 7.68 (m, 9H). 26

1.40-1.42 (m, 3H), 1.74- 2.21 (m, 8H), 3.30 (q, J = 6.8 Hz, 1H), 4.00-4.11 (m, 2H), 4.72-4.77 (m, 1H), 5.76 (brs, 1H), 6.94-7.68 (m, 9H). 27

1.09 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.34 (q, J = 7.0 Hz, 1H), 3.38 (q, J = 7.0 Hz, 2H), 3.68 (t, J = 5.1 Hz, 2H), 4.04 (d, J = 14.8 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 4.19-4.26 (m, 2H), 5.40 (brs, 1H), 6.90-7.00 (m, 4H), 7.23 (brs, 1H), 7.24- 7.30 (m, 2H), 7.69 (m, 1H). 28

1.09 (t, J = 7.0 Hz, 3H), 3.39 (q, J = 7.0 Hz, 1H), 3.42 (s, 2H), 3.69 (t, J = 5.0 Hz, 2H), 4.10 (s, 2H), 4.27 (t, J = 5.0 Hz, 2H), 6.90-7.00 (m, 4H), 7.18 (brs, 1H), 7.24-7.30 (m, 3H), 7.68 (m, 1H). 29

1.08 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.8 Hz, 3H), 3.30-3.42 (m, 3H), 3.68-3.70 (m, 2H), 4.04 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.21-4.32 (m, 2H), 5.73 (brs, 1H), 6.86-7.05 (m, 5H), 7.20-7.27 (m, 2H), 7.71 (m, 1H).

TABLE 5 Example structural formula ¹H-NMR (CDCl₃) 30

1.09 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 3.39 (q, J = 7.0 Hz, 2H), 3.70 (t, J = 5.0 Hz, 2H), 4.04 (s, 2H), 4.27 (t, J = 5.0 Hz, 2H), 5.49 (brs, 1H), 6.85-7.06 (m, 5H), 7.23 (t, J = 8.1 Hz, 1H), 7.48 (brs, 1H), 7.71 (d, J = 8.4 Hz, 1H). 31

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.33 (q, J = 7.0 Hz, 1H), 3.38 (q, J = 7.0 Hz, 2H), 3.68 (t, J = 5.0 Hz, 2H), 4.03 (d, J = 14.8 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 4.22 (dt, J = 15.1, 5.0 Hz, 1H), 4.28 (dt, J = 15.1, 5.0 Hz, 1H), 5.63 (brs, 1H), 6.89-7.19 (m, 5H), 7.26 (brs, 1H), 7.47 (dd, J = 7.9, 1.6 Hz, 1H), 7.68 (dd, J = 8.4, 0.7 Hz, 1H). 32

1.09 (t, J = 7.0 Hz, 3H), 1.46 (s, 6H), 3.38 (q, J = 7.0 Hz, 2H), 3.69 (t, J = 5.1 Hz, 2H), 4.03 (s, 2H), 4.25 (t, J = 5.1 Hz, 2H), 5.55 (brs, 1H), 6.89-7.18 (m, 5H), 7.45-7.48 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H). 33

1.47 (s, 6H), 1.86-2.04 (m, 2H), 2.45-2.57 (m, 2H), 2.77- 2.92 (m, 2H), 3.96 (s, 2H), 4.85 (m, 1H), 5.46 (brs, 1H), 6.94-7.11 (m, 4H), 7.29-7.37 (m, 4H), 7.67 (d, J = 8.8 Hz, 1H). 34

1.42 (d, J = 7.0 Hz, 3H), 1.82- 2.04 (m, 2H), 2.44-2.58 (m, 2H), 2.76-2.91 (m, 2H), 3.30 (q, J = 7.0 Hz, 1H), 3.99 (d, J = 14.1 Hz, 1H), 4.06 (d, J = 14.1 Hz, 1H), 4.87 (m, 1H), 5.52 (brs, 1H), 6.94-7.11 (m, 4H), 7.13 (brs, 1H), 7.30-7.37 (m, 3H), 7.66 (d, J = 8.8 Hz, 1H). 35

1.46 (s, 6H), 1.57 (m, 1H), 1.82-2.10 (m, 3H), 3.67-3.84 (m, 2H), 3.96-4.25 (m, 5H), 5.36 (brs, 1H), 6.96-7.11 (m, 5H), 7.28-7.35 (m, 2H), 7.48 (brs, 1H), 7.68 (d, J = 8.6 Hz, 1H).

TABLE 6 Example structural formula ¹H-NMR (CDCl₃) δ 36

1.08 (t, J = 7.0 Hz, 3H), 1.40 (d, J = 7.0 Hz, 3H), 3.33 (q, J = 7.0 Hz, 1H), 3.38 (q, J = 7.0 Hz, 2H), 3.68 (t, J = 5.0 Hz, 2H), 4.03 (d, J = 14.7 Hz, 1H), 4.12 (d, J = 14.7 Hz, 1H), 4.17- 4.32 (m, 2H), 5.95 (brs, 1H), 6.98-7.10 (m, 5H), 7.29-7.35 (m, 3H), 7.68 (m, 1H). 37

1.01 (t, J = 7.3 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H), 1.70-1.84 (m, 2H), 3.15 (t, J = 6.3 Hz, 1H), 3.37 (q, J = 7.3 Hz, 2H), 3.68 (t, J = 5.2 Hz, 2H), 4.01 (d, J = 14.6 Hz, 1H), 4.13 (d, J = 14.6 Hz, 1H), 4.21 (dt, J = 15.2, 5.2 Hz, 1H), 4.30 (dt, J = 15.2, 5.2 Hz, 1H), 5.56 (brs, 1H), 6.98-7.11 (m, 5H), 7.18 (brs, 1H), 7.27-7.35 (m, 2H), 7.68 (m, 1H). 38

0.99 (d, J 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H), 2.08 (m, 1H), 2.97 (d, J = 5.3 Hz, 1H), 3.37 (q, J = 7.0 Hz, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.99 (d, J = 14.4 Hz, 1H), 4.14 (d, J = 14.4 Hz, 1H), 4.22 (dt, J = 15.2, 5.2 Hz, 1H), 4.35 (dt, J = 15.2, 5.2 Hz, 1H), 5.80 (brs, 1H), 6.97-7.11 (m, 6H), 7.27-7.35 (m, 2H), 7.68 (m, 1H). 39

1.09 (t, J = 7.0 Hz, 3H), 1.46 (s, 6H), 3.39 (q, J = 7.0 Hz, 2H), 3.68 (t, J = 5.0 Hz, 2H), 4.03 (s, 2H), 4.24 (t, J = 5.0 Hz, 2H), 5.76 (brs, 1H), 6.97-7.10 (m, 5H), 7.27-7.35 (m, 2H), 7.51 (brs, 1H), 7.69 (m, 1H). 40

1.08 (t, J = 7.0 Hz, 3H), 2.43 (s, 3H), 3.20 (s, 2H), 3.38 (q, J = 7.0 Hz, 2H), 3.71 (t, J = 5.2 Hz, 2H), 3.96 (s, 2H), 4.37 (t, J = 5.2 Hz, 2H), 5.84 (brs, 1H), 6.98-7.11 (m, 5H), 7.27-7.35 (m, 2H), 7.38 (brs, 1H), 7.69 (m, 1H). 41

1.01 (t, J = 7.4 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H), 1.69-1.86 (m, 2H), 3.15 (t, J = 6.3 Hz, 1H), 3.37 (q, J = 7.0 Hz, 2H), 3.68 (t, J = 5.0 Hz, 2H), 4.00 (d, J = 14.6 Hz, 1H), 4.12 (d, J = 14.6 Hz, 1H), 4.19-4.33 (m, 2H), 5.79 (brs, 1H), 6.94-7.05 (m, 6H), 7.18 (brs, 1H), 7.67 (m, 1H).

TABLE 7 Example structural formula ¹H-NMR (CDCl₃) δ 42

1.08 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 2.33 (s, 3H), 3.33 (q, J = 6.9 Hz, 1H), 3.37 (q, J = 7.0 Hz, 2H), 3.67 (t, J = 5.1 Hz, 2H), 4.03 (d, J = 14.7 Hz, 1H), 4.11 (d, J = 14.7 Hz, 1H), 4.18- 4.32 (m, 2H), 5.62 (brs, 1H), 6.87-7.00 (m, 4H), 7.09-7.16 (m, 2H), 7.26 (brs, 1H), 7.65 (d, J = 9.4 Hz, 1H). 43

1.08 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 3.34 (q, J = 6.9 Hz, 1H), 3.38 (q, J = 7.0 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 4.04 (d, J = 14.7Hz, 1H), 4.13 (d, J = 14.7 Hz, 1H), 4.19-4.36 (m, 2H), 5.75 (brs, 1H), 6.94- 7.04 (m, 4H), 7.13-7.20 (m, 2H), 7.25 (brs, 1H), 7.69 (d, J = 8.6 Hz, 1H). 44

1.09 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 2.27 (brs, 1H), 3.34 (q, J = 7.0 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.70 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H), 4.23- 4.35 (m, 2H), 5.80 (brs, 1H), 6.51-6.64 (m, 2H), 6.92-7.08 (m, 2H), 7.21 (brs, 1H), 7.72 (d, J = 8.6 Hz, 1H). 45

1.08 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H), 1.94 (brs, 1H), 3.34 (q, J = 6.9 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.70 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H), 4.20- 4.37 (m, 2H), 5.63 (brs, 1H), 6.95-7.03 (m, 3H), 7.08 (d, J = 1.8 Hz, 1H), 7.19 (brs, 1H), 7.55-7.63 (m, 2H), 7.74 (d, J = 8.8 Hz, 1H). 46

1.08 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 2.32 (brs, 1H), 3.34 (q, J = 7.0 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.70 (t, J = 5.1 Hz, 2H), 4.05 (d, J = 14.7 Hz, 1H), 4.14 (d, J = 14.7 Hz, 1H), 4.20- 4.37 (m, 2H), 5.64 (brs, 1H), 6.97- 7.08 (m, 4H), 7.22 (brs, 1H), 7.56 (brd, J = 8.4 Hz, 2H), 7.72 (d, J = 8.6 Hz, 1H). 47

1.14 (t, J = 7.0 Hz, 3H), 1.39 (d, J = 7.0 Hz, 3H), 1.99 (m, 2H), 3.28- 3.41 (m, 5H), 3.99 (d, J = 14.6 Hz, 1H), 4.05 (d, J = 14.6 Hz, 1H), 4.18 (t, J = 7.0 Hz, 2H), 5.41 (brs, 1H), 6.71-7.02 (m, 6H), 7.16 (brs, 1H), 7.63 (d, J = 8.6 Hz, 1H).

TABLE 8 Example structural formula ¹H-NMR (CDCl₃) δ 48

1.09 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.33 (q, J = 7.0 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.69 (t, J = 5.1 Hz, 2H), 4.04 (d, J = 14.8 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 4.20-4.33 (m, 2H), 5.43 (br, 1H), 6.71 (m, 1H), 6.80 (m, 1H), 6.95-7.00 (m, 2H), 7.10 (q, J = 9.0 Hz, 1H), 7.22 (br, 1H), 7.69 (d, J = 8.3 Hz, 1H). 49

1.08 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.33 (q, J = 7.0 Hz, 1H), 3.38 (q, J = 7.0 Hz, 2H), 3.68 (t, J = 5.0 Hz, 2H), 4.03 (d, J = 14.8 Hz, 1H), 4.11 (d, J = 14.8 Hz, 1H), 4.18-4.32 (m, 2H), 5.41 (br, 1H), 6.83 (m, 1H), 6.91-7.05 (m, 4H), 7.22 (br, 1H), 7.65 (m, 1H). 50

1.21 (s, 3H), 1.29 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H), 3.35 (q, J = 6.9 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 4.10 (s, 2H), 4.11 (d, J = 13.9 Hz, 1H), 5.87 (brs, 1H), 6.91-7.05 (m, 6H), 7.09 (brs, 1H), 7.63 (d, J = 9.3 Hz, 1H). 51

1.40 (d, J = 7.0 Hz, 3H), 1.55 (m, 1H), 1.77-1.94 (m, 2H), 1.97-2.12 (m, 2H), 3.34 (q, J = 7.0 Hz, 1H), 3.65-3.83 (m, 2H), 3.96- 4.27 (m, 5H), 5.67 (brs, 1H), 6.91-7.06 (m, 6H), 7.24 (brs, 1H), 7.66 (dd, J = 8.4, 0.6 Hz, 1H). 52

1.07 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.33 (q, J = 7.0 Hz, 1H), 3.38 (q, J = 7.0 Hz, 2H), 3.68 (t, J = 5.1 Hz, 2H), 4.03 (d, J = 14.7 Hz, 1H), 4.12 (d, J = 14.7 Hz, 1H), 4.18- 4.32 (m, 2H), 5.43 (br, 1H), 6.95-7.23 (m, 6H), 7.25 (br, 1H), 7.66 (m, 1H). 53

1.09 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.34 (q, J = 7.0 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.19- 4.35 (m, 2H), 5.44 (br, 1H), 6.64-6.81 (m, 3H), 6.98-7.06 (m, 2H), 7.20-7.30 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H).

TABLE 9 Example structural formula ¹H-NMR (CDCl₃) δ 54

1.09 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.8 Hz, 3H), 3.33 (q, J = 6.8 Hz, 1H), 3.38 (q, J = 7.0 Hz, 2H), 3.68 (t, J = 5.2 Hz, 2H), 4.03 (d, J = 14.7 Hz, 1H), 4.12 (d, J = 14.7 Hz, 1H), 4.16- 4.32 (m, 2H), 5.41 (brs, 1H), 6.93-7.05 (m, 6H), 7.23 (brs, 1H), 7.67 (m, 1H). 55

1.09 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.33 (q, J = 7.0 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 4.04 (d, J = 14.8 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 4.19-4.34 (m, 2H), 5.35 (br, 1H), 6.79-7.13 (m, 4H), 7.20 (br, 1H), 7.69 (d, J = 8.6 Hz, 1H). 56

1.41 (d, J = 6.8 Hz, 3H), 1.50- 2.10 (m, 4H), 3.32 (q, J = 6.8 Hz, 1H), 3.66-3.84 (m, 2H), 4.01-4.23 (m, 5H), 5.44 (br, 1H), 6.93-7.05 (m, 6H), 7.25 (m, 1H), 7.66 (d, J = 6.4 Hz, 1H). 57

1.08 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 3.34 (q, J = 6.8 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.70 (t, J = 5.1 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.20-4.35 (m, 2H), 5.47 (br, 1H), 6.39 (m, 1H), 6.65 (m, 1H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.20 (br, 1H), 7.72 (d, J = 8.8 Hz, 1H). 58

1.08 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.8 Hz, 3H), 3.33 (q, J = 6.8 Hz, 1H), 3.38 (q, J = 7.0 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 4.03 (d, J = 14.8 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 4.19- 4.34 (m, 2H), 5.52 (br, 1H), 6.72 (m, 1H), 6.87-7.04 (m, 4H), 7.23 (br, 1H), 7.68 (d, J = 8.6 Hz, 1H).

Reference Example 8

To a solution of the compound (0.22 g, 0.66 mmol) obtained in Reference Example 6 in tetrahydrofuran (3 mL) was added phosphorus tribromide (0.18 g, 0.66 mmol) under ice-cooling. After stirring for 1 hr, aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was directly used for the next reaction.

¹H-NMR (CDCl₃) δ 1.08 (t, J=7.0 Hz, 3H), 3.39 (q, J=7.0 Hz, 2H), 3.70 (t, J=5.1 Hz, 2H), 4.37 (t, J=5.1 Hz, 2H), 4.81 (s, 2H), 6.95-7.05 (m, 6H), 7.69 (m, 1H).

Example 59 N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

To a solution of the compound (107 mg, 0.27 mmol) obtained in Reference Example 8 in acetonitrile (3 mL) were added diisopropylethylamine (0.10 ml, 0.55 mmol) and N-(2,4-dimethoxybenzyl)alaninamide (97.7 mg, 0.41 mmol). After stirring at 50° C. for 5 hr, aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. Trifluoroacetic acid (3 mL) was added thereto, and the mixture was further stirred at 50° C. for 2 hr, neutralized with aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from chloroform/2-propanol to give the object product (75 mg, 70%).

¹H-NMR (CDCl₃) δ1.08 (t, J=7.0 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H), 3.33-3.41 (m, 3H), 3.68 (t, J=5.1 Hz, 2H), 4.03 (d, J=14.6 Hz, 1H), 4.12 (d, J=14.6 Hz, 1H), 4.23-4.27 (m, 2H), 5.58 (brs, 1H), 6.94-7.05 (m, 6H), 7.24 (brs, 1H), 7.67 (m, 1H).

Examples 60-65

The compounds of Examples 60-65 shown in Table 10 were prepared in the same manner as in Reference Examples 1-4, 8 and Example 59 from 2,4-difluoronitrobenzene and using commercially available or known compounds.

TABLE 10 Example structural formula ¹H-NMR (CDCl₃) δ 60

1.41 (d, J = 7.0 Hz, 3H), 3.26 (s, 3H), 3.33 (q, J = 7.0 Hz, 1H), 3.65 (t, J = 4.9 Hz, 2H), 4.02 (d, J = 14.6 Hz, 1H), 4.10 (d, J = 14.6 Hz, 1H), 4.22- 4.28 (m, 2H), 5.34 (brs, 1H), 6.94-7.05 (m, 6H), 7.25 (brs, 1H), 7.67 (m, 1H). 61

1.02 (d, J = 6.2 Hz, 6H), 3.40- 3.48 (m, 3H), 3.68 (t, J = 5.1 Hz, 2H), 4.10 (s, 2H), 4.24 (t, J = 5.1 Hz, 2H), 5.45 (brs, 1H), 6.94-7.05 (m, 6H), 7.21 (brs, 1H), 7.67 (m, 1H). 62

1.01 (d, J = 6.0 Hz, 6H), 1.41 (d, J = 7.0 Hz, 3H), 3.33 (q, J = 7.0 Hz, 1H), 3.43 (m, 1H), 3.67 (t, J = 5.1 Hz, 2H), 4.04 (d, J = 14.8 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 4.22 (m, 2H), 5.33 (brs, 1H), 6.93-7.05 (m, 6H), 7.26 (brs, 1H), 7.67 (m, 1H). 63

3.25 (s, 3H), 3.40 (s, 2H), 3.64 (t, J = 5.0 Hz, 2H), 4.08 (s, 2H), 4.26 (t, J = 5.0 Hz, 2H), 6.34 (brs, 1H), 6.93-7.04 (m, 6H), 7.21 (brs, 1H), 7.65 (m, 1H). 64

1.42 (d, J = 7.0 Hz, 3H), 2.02 (quint, J = 6.7 Hz, 2H), 3.28 (s, 3H), 3.27-3.37 (m, 3H), 4.01 (d, J = 14.6 Hz, 1H), 4.07 (d, J = 14.6 Hz, 1H), 4.19 (t, J = 6.7 Hz, 2H), 5.36 (brs, 1H), 6.93-7.05 (m, 6H), 7.21 (brs, 1H), 7.66 (d, J = 8.8 Hz, 1H). 65

1.82-1.87 (m, 2H), 2.43-2.57 (m, 2H), 3.43 (s, 2H), 3.51-3.59 (m, 2H), 4.11 (s, 2H), 4.14-4.19 (m, 2H), 4.49 (m, 1H), 5.46 (brs, 1H), 6.80 (brs, 1H), 6.91- 7.05 (m, 5H), 7.25 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H).

Reference Example 9

The object product was obtained in the same manner as in Reference Examples 1, 3 and 4 from 2-fluoro-4-bromonitrobenzene.

¹H-NMR (CDCl₃) δ 1.12 (t, J=7.0 Hz, 3H), 3.43 (q, J=7.0 Hz, 2H), 3.75 (t, J=5.1 Hz, 2H), 4.37 (t, J=5.1 Hz, 2H), 4.88 (s, 2H), 7.36 (dd, J=8.6, 1.8 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H).

Reference Example 10

The object product was obtained in the same manner as in Reference Example 5 from the compound obtained in Reference Example 9.

¹H-NMR (CDCl₃) δ 1.02 (t, J=7.0 Hz, 3H), 3.35 (q, J=7.0 Hz, 2H), 3.71 (t, J=5.1 Hz, 2H), 4.64 (t, J=5.1 Hz, 2H), 7.41 (m, 1H), 7.68-7.73 (m, 2H), 10.05 (s, 1H).

Reference Example 11

To a solution (4:1, 15 mL) of the compound (200 mg, 0.67 mmol) obtained in Reference Example 10 in a mixed solvent of dioxane-water were added potassium carbonate (280 mg, 2.02 mmol), phenylboronic acid (123 mg, 1.01 mmol) and tetrakis(triphenylphosphine)palladium (154 mg, 0.13 mmol), and the mixture was heated to 110° C. After refluxing for 2 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane:ethyl acetate=90:10-75:25-50:50) to give the object product (115 mg, 58%).

¹H-NMR (CDCl₃) δ 1.07 (t, J=7.0 Hz, 3H), 3.42 (q, J=7.0 Hz, 2H), 3.81 (t, J=5.1 Hz, 2H), 4.81 (t, J=5.1 Hz, 2H), 7.39 (m, 1H), 7.48 (t, J=7.6 Hz, 2H), 7.63-7.67 (m, 3H), 7.76 (m, 1H), 7.96 (d, J=8.6 Hz, 1H), 10.11 (s, 1H).

Example 66 N²-{[1-(2-ethoxyethyl)-6-phenyl-1H-benzimidazol-2-yl]methyl}glycinamide

The object product (31 mg, 38%) was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 11 (68 mg, 0.23 mmol).

¹H-NMR (CDCl₃) δ1.08 (t, J=7.1 Hz, 3H), 3.38 (q, J=7.1 Hz, 2H), 3.41 (s, 2H), 3.75 (t, J=5.1 Hz, 2H), 4.11 (s, 2H), 4.35 (t, J=5.1 Hz, 2H), 5.68 (brs, 1H), 7.22 (brs, 1H), 7.33 (m, 1H), 7.42-7.51 (m, 4H), 7.61-7.63 (m, 2H), 7.76 (m, 1H).

Examples 67-73

The compounds of Examples 67-73 shown in Table 11 and Table 12 were prepared in the same manner as in Reference Examples 9-11 and Example 66.

TABLE 11 Example structural formula ¹H-NMR (CDCl₃) δ 67

1.03 (t, J = 7.1 Hz, 3H), 3.29 (q, J = 7.1 Hz, 2H), 3.36 (s, 2H), 3.70 (t, J = 5.1 Hz, 2H), 4.06 (s, 2H), 4.30 (t, J = 5.1 Hz, 2H), 5.68 (brs, 1H), 7.06-7.09 (m, 2H), 7.16 (brs, 1H), 7.37- 7.39 (m, 2H), 7.49-7.53 (m, 2H), 7.70 (m, 1H). 68

1.08 (t, J = 7.1 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H), 3.32 (q, J = 6.8 Hz, 1H), 3.37 (q, J = 7.1 Hz, 2H), 3.73 (t, J = 5.0 Hz, 2H), 4.04 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.31 (dt, J = 15.9, 5.0 Hz, 1H), 4.36 (dt, J = 15.9, 5.0 Hz, 1H), 5.61 (brs, 1H), 7.10-7.14 (m, 2H), 7.25 (brs, 1H), 7.41-7.43 (m, 2H), 7.54- 7.57 (m, 2H), 7.74 (m, 1H). 69

1.08 (t, J = 7.0 Hz, 3H), 1.39 (d, J = 6.9 Hz, 3H), 3.30 (q, J = 6.9 Hz, 1H), 3.37 (q, J = 7.0 Hz, 2H), 3.73 (t, J = 4.8 Hz, 2H), 4.04 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.28-4.38 (m, 2H), 5.73 (brs, 1H), 7.28 (brs, 1H), 7.33 (m, 1H), 7.41-7.50 (m, 4H), 7.60- 7.63 (m, 2H), 7.75 (m, 1H). 70

1.10 (t, J = 7.0 Hz, 3H), 3.40 (q, J = 7.0 Hz, 2H), 3.44 (s, 2H), 3.75 (t, J = 5.0 Hz, 2H), 4.14 (s, 2H), 4.36 (t, J = 5.0 Hz, 2H), 5.60 (brs, 1H), 7.27-7.36 (m, 4H), 7.40-7.43 (m, 2H), 7.50 (m, 1H), 7.78 (m, 1H).

TABLE 12 Example structural formula ¹H-NMR (CDCl₃) δ 71

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.35 (q, J = 7.0 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.74 (t, J = 5.0 Hz, 2H), 4.07 (d, J = 14.7 Hz, 1H), 4.16 (d, J = 14.7 Hz, 1H), 4.30 (dt, J = 15.0, 5.0 Hz, 1H), 4.37 (dt, J = 15.0, 5.0 Hz, 1H), 5.81 (brs, 1H), 7.26-7.36 (m, 4H), 7.39-7.42 (m, 2H), 7.50 (m, 1H), 7.78 (m, 1H). 72

1.10 (t, J = 7.0 Hz, 3H), 3.40 (q, J = 7.0 Hz, 2H), 3.43 (s, 2H), 3.77 (t, J = 5.1 Hz, 2H), 4.13 (s, 2H), 4.38 (t, J = 5.1 Hz, 2H), 5.65 (brs, 1H), 7.21 (brs, 1H), 7.41-7.49 (m, 4H), 7.54-7.58 (m, 2H), 7.78 (m, 1H). 73

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.35 (q, J = 7.0 Hz, 1H), 3.40 (q, J = 7.0 Hz, 2H), 3.76 (t, J = 5.0 Hz, 2H), 4.06 (d, J = 14.7 Hz, 1H), 4.16 (d, J = 14.7 Hz, 1H), 4.31- 4.44 (m, 2H), 5.81 (brs, 1H), 7.28 (brs, 1H), 7.40-7.47 (m, 4H), 7.53-7.57 (m, 2H), 7.78 (m, 1H).

Reference Example 12

Under a nitrogen atmosphere, to a solution of the compound (150 mg, 0.5 mmol) obtained in Reference Example 9 in N-methylpyrrolidinone (5 mL) were added cesium carbonate (489 mg, 1.5 mmol), 4-tert-butylphenol (225 mg, 1.5 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (52 μl, 0.25 mmol) and copper(I) chloride (50 mg, 0.5 mmol), and the mixture was heated to 120° C. After stirring for 6 hr, the reaction mixture was added to 2 mol/L hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 mol/L hydrochloric acid, 2 mol/L aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane:ethyl acetate=100:0-0:100) to give the object product (56 mg, 30%).

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.32 (s, 9H), 3.41 (q, J=7.0 Hz, 2H), 3.72 (t, J=5.1 Hz, 2H), 4.35 (t, J=5.1 Hz, 2H), 4.89 (s, 2H), 6.89-7.02 (m, 4H), 7.31-7.36 (m, 2H), 7.64 (d, J=8.5 Hz, 1H).

Example 74 N²-{[6-(4-tert-butylphenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Reference Example 5 and Example 1 from the compound obtained in Reference Example 12.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.32 (s, 9H), 1.41 (d, J=6.9 Hz, 3H), 3.34 (q, J=6.9 Hz, 1H), 3.38 (q, J=7.0 Hz, 2H), 3.68 (t, J=5.1 Hz, 2H), 4.04 (d, J=14.9 Hz, 1H), 4.12 (d, J=14.9 Hz, 1H), 4.18-4.34 (m, 2H), 5.47 (brs, 1H), 6.89-6.95 (m, 2H), 6.97-7.02 (m, 2H), 7.29 (brs, 1H), 7.31-7.36 (m, 2H), 7.67 (d, J=8.5 Hz, 1H).

Reference Example 13

To a solution of the compound (1.20 g, 4 mmol) obtained in Reference Example 9 in N,N-dimethylformamide (15 mL) were added imidazole (1.36 g, 20 mmol) and tert-butyldimethylsilyl chloride (904 mg, 6 mmol). After stirring at room temperature for 2 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane:ethyl acetate=100:0-85:15) to give the object product (1.65 g, 100%).

¹H-NMR (CDCl₃) δ0.11 (s, 6H), 0.91 (s, 9H), 1.12 (t, J=7.0 Hz, 3H), 3.41 (q, J=7.0 Hz, 2H), 3.74 (t, J=5.5 Hz, 2H), 4.44 (t, J=5.5 Hz, 2H), 4.99 (s, 2H), 7.34 (dd, J=1.9, 8.5 Hz, 1H), 7.56-7.62 (m, 2H).

Reference Example 14

Under a nitrogen atmosphere, to a solution of the compound (207 mg, 0.5 mmol) obtained in Reference Example 13 in N-methylpyrrolidinone (5 mL) were added cesium carbonate (489 mg, 1.5 mmol), 4-methoxyphenol (186 mg, 1.5 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (52 μl, 0.25 mmol) and copper(I) chloride (50 mg, 0.5 mmol), and the mixture was heated to 120° C. After stirring for 4 hr, the reaction mixture was added to 2 mol/L hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 mol/L hydrochloric acid, 2 mol/L aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane:ethyl acetate=100:0-0:100) to give the object product (36 mg, 21%).

¹H-NMR (CDCl₃) δ 1.10 (t, J=7.0 Hz, 3H), 3.41 (q, J=7.0 Hz, 2H), 3.70 (t, J=5.0 Hz, 2H), 3.81 (s, 3H), 4.32 (t, J=5.0 Hz, 2H), 4.88 (s, 2H), 6.84-7.01 (m, 6H), 7.63 (d, J=8.8 Hz, 1H).

Example 75 N²-{[1-(2-ethoxyethyl)-6-(4-methoxyphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Reference Example 5 and Example 1 from the compound obtained in Reference Example 14.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H), 3.33 (q, J=6.8 Hz, 1H), 3.37 (q, J=7.0 Hz, 2H), 3.67 (t, J=5.1 Hz, 2H), 3.81 (s, 3H), 4.03 (d, J=14.7 Hz, 1H), 4.10 (d, J=14.7 Hz, 1H), 4.17-4.30 (m, 2H), 5.32 (brs, 1H), 6.85-7.00 (m, 6H), 7.27 (brs, 1H), 7.64 (d, J=8.8 Hz, 1H).

Reference Example 15

To a solution of 3-fluoro-4-nitrophenol (2.5 g, 16.0 mmol) in N,N-dimethylformamide (30 mL) were added potassium carbonate (3.3 g, 24.0 mmol) and benzyl bromide (2.1 ml, 17.6 mmol), and the mixture was heated at 70° C. After stirring for 1 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure, and the obtained residue was directly used for the next reaction.

¹H-NMR (CDCl₃) δ5.14 (s, 2H), 6.79-6.86 (m, 2H), 7.38-7.43 (m, 5H), 8.10 (m, 1H).

Reference Example 16

The object product was obtained in the same manner as in Reference Examples 1 and 3-5 from the compound obtained in Reference Example 15.

¹H-NMR (CDCl₃) δ 1.08 (t, J=7.0 Hz, 3H), 3.40 (q, J=7.0 Hz, 2H), 3.77 (t, J=5.1 Hz, 2H), 4.71 (t, J=5.1 Hz, 2H), 5.15 (s, 2H), 7.04 (d, J=2.4 Hz, 1H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 7.35-7.49 (m, 5H), 7.79 (d, J=9.0 Hz, 1H), 10.01 (s, 1H).

Example 76 N²-{[6-(benzyloxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 16 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.39 (d, J=7.0 Hz, 3H), 3.32 (q, J=7.0 Hz, 1H), 3.37 (q, J=7.0 Hz, 2H), 3.68 (t, J=5.1 Hz, 2H), 4.00 (d, J=14.6 Hz, 1H), 4.09 (d, J=14.6 Hz, 1H), 4.16-4.32 (m, 2H), 5.11 (s, 2H), 5.75 (brs, 1H), 6.87 (d, J=2.2 Hz, 1H), 6.98 (dd, J=8.8, 2.2 Hz, 1H), 7.27-7.53 (m, 6H), 7.61 (d, J=8.8 Hz, 1H).

Example 77 N²-{[6-(benzyloxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 16 and 2-methylalaninamide.

¹H-NMR (CDCl₃) δ 1.10 (t, J=7.0 Hz, 3H), 1.45 (s, 6H), 3.37 (q, J=7.0 Hz, 2H), 3.69 (t, J=5.1 Hz, 2H), 4.00 (s, 2H), 4.24 (t, J=5.1 Hz, 2H), 5.12 (s, 2H), 5.47 (brs, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.98 (dd, J=8.8, 2.4 Hz, 1H), 7.31-7.48 (m, 5H), 7.51 (brs, 1H), 7.62 (d, J=8.8 Hz, 1H).

Reference Example 17

The object product was obtained in the same manner as in Reference Examples 15, 1 and 3-5 from 3-fluoro-4-nitrophenol.

¹H-NMR (CDCl₃) δ 1.07 (t, J=7.0 Hz, 3H), 3.40 (q, J=7.0 Hz, 2H), 3.78 (t, J=5.3 Hz, 2H), 4.71 (t, J=5.3 Hz, 2H), 5.10 (s, 2H), 7.03 (d, J=2.2 Hz, 1H), 7.07-7.13 (m, 3H), 7.42-7.47 (m, 2H), 7.79 (d, J=9.0 Hz, 1H), 10.01 (s, 1H).

Example 78 N²-({1-(2-ethoxyethyl)-6-[(4-fluorobenzyl)oxy]-1H-benzimidazol-2-yl}methyl)-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 17 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.10 (t, J=7.0 Hz, 3H), 1.40 (d, J=7.0 Hz, 3H), 3.32 (q, J=7.0 Hz, 1H), 3.38 (q, J=7.0 Hz, 2H), 3.70 (t, J=5.1 Hz, 2H), 4.01 (d, J=14.6 Hz, 1H), 4.09 (d, J=14.6 Hz, 1H), 4.20-4.32 (m, 2H), 5.08 (s, 2H), 5.39 (brs, 1H), 6.86 (d, J=2.2 Hz, 1H), 6.96 (dd, J=8.8, 2.2 Hz, 1H), 7.06-7.10 (m, 2H), 7.25 (brs, 1H), 7.42-7.45 (m, 2H), 7.62 (d, J=8.8 Hz, 1H).

Reference Example 18

To a solution of 2,6-dichloro-3-nitropyridine (3.0 g, 15.5 mmol) in dioxane (50 mL) were added potassium carbonate (2.4 g, 17.0 mmol) and 2-ethoxyethylamine (1.4 g, 17.0 mmol), and the mixture was stirred at 50° C. After stirring for 3 hr, potassium carbonate (1.8 g, 13.0 mmol) and 2-ethoxyethylamine (0.9 g, 10.0 mmol) were added thereto, and the mixture was stirred at 50° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate:hexane=1:5) to give the object product (3.4 g, 89%).

¹H-NMR (CDCl₃) δ 1.24 (t, J=7.0 Hz, 3H), 3.57 (q, J=7.0 Hz, 2H), 3.67 (t, J=5.2 Hz, 2H), 3.82 (q, J=5.2 Hz, 2H), 6.61 (d, J=8.5 Hz, 1H), 8.35 (d, J=8.5 Hz, 1H), 8.59 (br, 1H).

Reference Example 19

The object product was obtained in the same manner as in Reference Example 2 from the compound obtained in Reference Example 18.

¹H-NMR (CDCl₃) δ 1.18 (t, J=7.0 Hz, 3H), 3.39-3.50 (m, 6H), 6.20 (d, J=9.0 Hz, 1H), 7.12-7.17 (m, 2H), 7.25 (m, 1H), 7.37-7.44 (m, 2H), 8.42 (d, J=9.0 Hz, 1H), 8.66 (br, 1H).

Reference Example 20

The object product was obtained in the same manner as in Reference Examples 3-5 from the compound obtained in Reference Example 19.

¹H-NMR (CDCl₃) δ 1.01 (t, J=7.0 Hz, 3H), 3.38 (q, J=7.0 Hz, 2H), 3.72 (t, J=5.6 Hz, 2H), 4.70 (t, J=5.6 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 7.17-7.28 (m, 3H), 7.37-7.46 (m, 2H), 8.16 (d, J=8.8 Hz, 1H), 10.00 (s, 1H).

Example 79 N²-{[3-(2-ethoxyethyl)-5-phenoxy-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 1 from the compound obtained in Reference Example 20. ¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.41 (d, J=7.0 Hz, 3H), 3.35 (q, J=7.0 Hz, 1H), 3.38 (q, J=7.0 Hz, 2H), 3.71 (t, J=5.1 Hz, 2H), 4.06 (d, J=15.0 Hz, 1H), 4.14 (d, J=15.0 Hz, 1H), 4.32 (t, J=5.1 Hz, 2H), 5.56 (brs, 1H), 6.67 (d, J=8.6 Hz, 1H), 7.11-7.21 (m, 3H), 7.26 (brs, 1H), 7.35-7.42 (m, 2H), 7.95 (d, J=8.6 Hz, 1H).

Example 80 N²-{[3-(2-ethoxyethyl)-5-phenoxy-3H-imidazo[4,5-b]pyridin-2-yl]methyl}glycinamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 20. ¹H-NMR (CDCl₃) δ 1.08 (t, J=7.0 Hz, 3H), 3.38 (q, J=7.0 Hz, 2H), 3.42 (s, 2H), 3.72 (t, J=4.9 Hz, 2H), 4.12 (s, 2H), 4.33 (t, J=4.9 Hz, 2H), 5.73 (brs, 1H), 6.76 (d, J=8.4 Hz, 1H), 7.11-7.22 (m, 3H), 7.26 (brs, 1H), 7.35-7.42 (m, 2H), 7.95 (d, J=8.4 Hz, 1H).

Reference Example 21

The object product was obtained in the same manner as in Reference Example 1 from 2,4,5-trifluoronitrobenzene.

¹H-NMR (CDCl₃) δ 1.25 (t, J=7.1 Hz, 3H), 3.43 (q, J=5.1 Hz, 2H), 3.57 (q, J=7.1 Hz, 2H), 3.72 (t, J=5.1 Hz, 2H), 6.66 (dd, J=12.4, 6.6 Hz, 1H), 8.05 (dd, J=10.2, 8.6 Hz, 1H), 8.29 (br, 1H).

Reference Example 22

The object product was obtained in the same manner as in Reference Examples 2-5 from the compound obtained in Reference Example 21.

¹H-NMR (CDCl₃) δ 0.99 (t, J=7.0 Hz, 3H), 3.33 (q, J=7.0 Hz, 2H), 3.71 (t, J=5.1 Hz, 2H), 4.64 (t, J=5.1 Hz, 2H), 7.00-7.10 (m, 4H), 7.13 (d, J=7.1 Hz, 1H), 7.66 (d, J=10.3 Hz, 1H), 10.04 (s, 1H).

Example 81 N²-{[1-(2-ethoxyethyl)-5-fluoro-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 1 from the compound obtained in Reference Example 22.

¹H-NMR (CDCl₃) δ 1.07 (t, J=7.0 Hz, 3H), 1.41 (d, J=7.0 Hz, 3H), 3.32 (q, J=7.0 Hz, 1H), 3.37 (q, J=7.0 Hz, 2H), 3.66 (t, J=5.1 Hz, 2H), 4.02 (d, J=14.7 Hz, 1H), 4.11 (d, J=14.7 Hz, 1H), 4.17-4.32 (m, 2H), 5.38 (brs, 1H), 6.90-7.05 (m, 5H), 7.16 (brs, 1H), 7.52 (d, J=12.1 Hz, 1H).

Reference Example 23

The object product was obtained in the same manner as in Reference Examples 1-4 from 2,4-difluoronitrobenzene, 4-amino-(1-tert-butoxycarbonyl)piperidine and 4-fluorophenol.

¹H-NMR (CDCl₃) δ 1.48 (s, 9H), 1.91-1.95 (m, 2H), 2.22-2.37 (m, 2H), 2.76-2.93 (m, 2H), 4.30 (br, 2H), 4.60 (m, 1H), 4.86 (s, 2H), 6.86-7.05 (m, 5H), 7.14 (d, J=2.0 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H).

Reference Example 24

The object product was obtained in the same manner as in Reference Example 5 from the compound obtained in Reference Example 23.

¹H-NMR (CDCl₃) δ 1.48 (s, 9H), 1.89-1.93 (m, 2H), 2.23-2.38 (m, 2H), 2.85-2.94 (m, 2H), 4.33 (br, 2H), 5.63 (m, 1H), 6.99-7.10 (m, 5H), 7.18 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 10.04 (s, 1H).

Example 82 tert-butyl 4-[2-({[(2S)-1-amino-1-oxopropan-2-yl]amino}methyl)-6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]piperidine-1-carboxylate

The object product was obtained in the same manner as in Example 1 from the compound obtained in Reference Example 24.

¹H-NMR (CDCl₃) δ 1.38 (d, J=7.0 Hz, 3H), 1.48 (s, 9H), 1.86-1.89 (m, 2H), 2.30-2.34 (m, 2H), 2.81-2.89 (m, 2H), 3.28 (q, J=7.0 Hz, 1H), 4.02 (d, J=14.7 Hz, 1H), 4.10 (d, J=14.7 Hz, 1H), 4.31-4.42 (m, 3H), 6.02 (brs, 1H), 6.87-7.04 (m, 6H), 7.15 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H).

Example 83 N²-{[6-(4-fluorophenoxy)-1-(piperidin-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

To a solution of the compound (68 mg, 0.13 mmol) obtained in Example 82 in dichloromethane (1.3 mL) was added trifluoroacetic acid (260 μL), and the mixture was stirred at room temperature for 1 hr. Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate:methanol=99:1-80:20) to give the object product (38 mg, 71%).

¹H-NMR (CDCl₃) δ 1.41 (d, J=7.0 Hz, 3H), 1.86-1.89 (m, 2H), 2.26-2.40 (m, 2H), 2.72-2.81 (m, 2H), 3.26-3.33 (m, 3H), 4.02 (d, J=14.7 Hz, 1H), 4.10 (d, J=14.7 Hz, 1H), 4.30 (m, 1H), 5.89 (brs, 1H), 6.89-7.07 (m, 6H), 7.33 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H).

Reference Example 25

To a solution of the compound (300 mg, 0.68 mmol) obtained in Reference Example 24 in dichloromethane (6.8 mL) was added trifluoroacetic acid (1.4 mL), and the mixture was stirred at room temperature for 1 hr. Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (6.8 mL), triethylamine (142 μL, 1.02 mmol) and isopropyl isocyanate (100 μL, 1.02 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform:methanol=99:1-85:15) to give the object product (280 mg, 97%).

¹H-NMR (CDCl₃) δ 1.18 (d, J=6.6 Hz, 6H), 1.92-1.97 (m, 2H), 2.28-2.42 (m, 2H), 2.91-3.01 (m, 2H), 4.01 (m, 1H), 4.12-4.17 (m, 2H), 4.33 (m, 1H), 5.65 (m, 1H), 6.97-7.10 (m, 5H), 7.20 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 10.04 (s, 1H).

Example 84 4-[2-({[(2S)-1-amino-1-oxopropan-2-yl]amino}methyl)-6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-N-(propan-2-yl)piperidine-1-carboxamide

The object product was obtained in the same manner as in Example 1 from the compound obtained in Reference Example 25.

¹H-NMR (CDCl₃) δ 1.17 (d, J=6.6 Hz, 6H), 1.38 (d, J=7.0 Hz, 3H), 1.90-1.92 (m, 2H), 2.30-2.40 (m, 2H), 2.87-2.94 (m, 2H), 3.27 (q, J=7.0 Hz, 1H), 3.93-4.18 (m, 5H), 4.36-4.45 (m, 2H), 5.73 (brs, 1H), 6.89-7.03 (m, 6H), 7.16 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H).

Example 85 N²-{[1-(1-acetylpiperidin-4-yl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Reference Example 25 and Example 1 from the compound obtained in Reference Example 24 and acetyl chloride.

¹H-NMR (CDCl₃) δ 1.38 (d, J=7.0 Hz, 3H), 1.89-2.46 (m, 3H), 2.16 (s, 3H), 2.67 (m, 1H), 3.18-3.32 (m, 2H), 3.65 (m, 1H), 3.99-4.13 (m, 3H), 4.52 (m, 1H), 4.89 (m, 1H), 5.85 (brs, 1H), 6.88-7.05 (m, 6H), 7.11 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H).

Example 86 N²-({6-(4-fluorophenoxy)-1-[1-(methylsulfonyl)piperidin-4-yl]-1H-benzimidazol-2-yl}methyl)-L-alaninamide

The object product was obtained in the same manner as in Reference Example 25 and Example 1 from the compound obtained in Reference Example 24 and methanesulfonyl chloride.

¹H-NMR (CDCl₃) δ 1.37 (d, J=6.8 Hz, 3H), 2.00-2.16 (m, 3H), 2.48-2.61 (m, 2H), 2.88 (m, 1H), 2.86 (s, 3H), 3.25 (q, J=6.8 Hz, 1H), 3.99-4.16 (m, 4H), 4.46 (m, 1H), 5.87 (brs, 1H), 6.81 (brs, 1H), 6.89-7.05 (m, 5H), 7.21 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H).

Reference Example 26

To a solution of the compound (2.28 g, 6.9 mmol) obtained in Reference Example 7 in tetrahydrofuran (70 mL) were added (L)-alanine ethyl ester hydrochloride (2.15 g, 14 mmol), triethylamine (1.95 ml, 14 mmol) and sodium sulfate (10 g), and the mixture was stirred at room temperature. After stirring for 1 hr, sodium cyanoborohydride (503 mg, 8 mmol) was added thereto, and the mixture was stirred for 4 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform:methanol=100:0-95:5) to give the object product (1.78 g, 60%).

¹H-NMR (CDCl₃) δ 1.08 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.35 (d, J=7.0 Hz, 3H), 3.38 (q, J=7.0 Hz, 2H), 3.48 (q, J=7.1 Hz, 1H), 3.70 (t, J=5.3 Hz, 2H), 4.02 (d, J=13.9 Hz, 1H), 4.10-4.23 (m, 3H), 4.31-4.42 (m, 2H), 6.90-7.05 (m, 6H), 7.66 (d, J=8.6 Hz, 1H).

Reference Example 27

To a solution of the compound (2.79 g, 6.5 mmol) obtained in Reference Example 26 in acetonitrile (65 mL) was added di-t-butyl dicarbonate (1.64 g, 7.5 mmol), and the mixture was stirred with heating at 60° C. for 3 hr and at 100° C. for 3 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column (hexane:ethyl acetate=100:0-70:30) to give the object product (2.24 g, 65%).

¹H-NMR (CDCl₃) δ 1.00-1.18 (m, 6H), 1.40 (d, J=7.1 Hz, 3H), 1.44 (s, 9H), 3.38 (q, J=7.0 Hz, 2H), 3.68 (t, J=5.9 Hz, 2H), 3.86-4.12 (m, 2H), 4.19-4.55 (m, 3H), 4.75 (d, J=15.4 Hz, 1H), 4.98 (d, J=15.4 Hz, 1H), 6.90-7.08 (m, 6H), 7.64 (d, J=8.8 Hz, 1H).

Reference Example 28

To a solution of the compound (2.24 g, 4.2 mmol) obtained in Reference Example 27 in ethanol (40 mL) was added 2 mol/L aqueous sodium hydroxide solution (4.2 ml, 8.4 mmol) in an ice bath. After stirring for 30 min under the same conditions, water was added to the reaction mixture, and the aqueous layer was washed with ether. The aqueous layer was adjusted to pH=4 with 2 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was extracted, washed with saturated brine and dried over sodium sulfate to give the object product (2.02 g, 96%).

¹H-NMR (CDCl₃) δ 1.11 (t, J=7.0 Hz, 3H), 1.49 (s, 9H), 1.55 (d, J=7.2 Hz, 3H), 3.30-3.50 (m, 2H), 3.63-3.75 (m, 2H), 3.90 (brs, 1H), 4.13-4.29 (m, 2H), 4.54 (brs, 1H), 5.27 (brs, 1H), 6.91-7.08 (m, 6H), 7.63 (d, J=8.6 Hz, 1H).

Example 87 N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-N-(2-hydroxy-2-methylpropyl)-L-alaninamide

To a solution of the compound (53 mg, 0.1 mmol) obtained in Reference Example 28 in dichloromethane (2 mL) were added 1-amino-2-methylpropan-2-ol (18 mg, 0.2 mmol) and PyBOP [registered trade mark, benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate)] (52 mg, 0.1 mmol), and the mixture was stirred at room temperature. After 16 hr, 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column (chloroform:methanol=100:0-98:2) to give the object product (51 mg, 89%). The product was dissolved in ethyl acetate (1 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (1 ml, 4 mmol) was added thereto, and the mixture was stirred at room temperature. After 14 hr, the mixture was concentrated under reduced pressure. To the obtained residue was added 2 mol/L aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was extracted, washed with saturated brine, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column (chloroform:methanol=100:0-95:5) to give the object product (32 mg, 76%).

¹H-NMR (CDCl₃) δ 1.10 (t, J=7.0 Hz, 3H), 1.29 (s, 6H), 1.36 (d, J=6.8 Hz, 3H), 3.21 (dd, J=5.3, 3.6 Hz, 1H), 3.29-3.51 (m, 4H), 3.61-3.73 (m, 2H), 3.97 (d, J=14.3 Hz, 1H), 4.11 (d, J=14.3 Hz, 1H), 4.21 (dt, J=15.3, 4.2 Hz, 1H), 4.33 (m, 1H), 6.90-7.07 (m, 6H), 7.68 (dd, J=8.3, 0.9 Hz, 1H), 7.83 (brt, J=6.0 Hz, 1H).

Examples 88-90

The compounds of Examples 88-90 shown in Table 13 were prepared according to the methods described in the above-mentioned Reference Examples and Examples or methods analogous thereto.

TABLE 13 Example structural formula ¹H-NMR (CDCl₃) δ 88

1.08 (t, J = 7.0 Hz, 3H), 1.37 (d, J = 7.0 Hz, 3H), 3.32 (q, J = 7.0 Hz, 1H), 3.35 (s, 3H), 3.38 (q, J = 7.0 Hz, 2H), 3.43-3.52 (m, 4H), 3.67 (t, J = 5.2 Hz, 2H), 3.99 (d, J = 14.7 Hz, 1H), 4.08 (d, J = 14.7 Hz, 1H), 4.26 (t, J = 5.2 Hz, 2H), 6.91-7.07 (m, 6H), 7.53 (brs, 1H), 7.64- 7.69 (m, 1H). 89

1.08 (t, J = 7.1 Hz, 3H), 1.37 (d, J = 6.8 Hz, 3H), 2.41-2.53 (m, 6H), 3.25- 3.45 (m, 5H), 3.62-3.72 (m, 6H), 4.00 (d, J = 14.9 Hz, 1H), 4.08 (d, J = 14.9 Hz, 1H), 4.17- 4.33 (m, 2H), 6.94-7.05 (m, 6H), 7.48 (brt, J = 5.2 Hz, 1H), 7.66 (m, 1H). 90

1.08 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 7.0 Hz, 3H), 3.31-3.43 (m, 3H), 3.44- 3.80 (m, 10H), 3.96 (d, J = 14.1 Hz, 1H), 4.11 (d, J = 14.1 Hz, 1H), 4.32 (m, 1H), 4.46 (m, 1H), 6.90-7.06 (m, 6H), 7.63 (d, J = 8.6 Hz, 1H).

Reference Example 29

To a solution of alcohol (500 mg, 1.58 mmol) obtained in the same manner as in Reference Examples 1-4 in dichloromethane (16 mL) was added thionyl chloride (342 μL, 4.74 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the obtained residue was dissolved in chloroform, aqueous sodium hydroxide solution was added thereto. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the object product (508 mg, 96%).

¹H-NMR (CDCl₃) δ 3.27 (s, 3H), 3.67 (t, J=5.1 Hz, 2H), 4.38 (t, J=5.1 Hz, 2H), 4.92 (s, 2H), 6.96-7.06 (m, 6H), 7.58 (d, J=8.4 Hz, 1H).

Example 91 N²-{[6-(4-fluorophenoxy)-1-(2-methoxyethyl)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide

To a solution of the compound (300 mg, 0.90 mmol) obtained in Reference Example 29 in acetonitrile (4.5 mL) were added 2,2-dimethylglycine (138 mg, 1.35 mmol), diisopropylethylamine (321 μL, 1.80 mmol) and sodium iodide (135 mg, 0.90 mmol), and the mixture was heated to 50° C. and stirred overnight. Water was added thereto, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate:methanol=99:1-80:20) to give the object product (169 mg, 47%).

¹H-NMR (CDCl₃) δ 1.45 (s, 6H), 3.26 (s, 3H), 3.66 (t, J=5.0 Hz, 2H), 4.00 (s, 2H), 4.25 (t, J=5.0 Hz, 2H), 5.57 (brs, 1H), 6.94-7.05 (m, 6H), 7.46 (brs, 1H), 7.67 (m, 1H).

Reference Example 30

To a solution of the compound (0.84 g, 2.8 mmol) obtained in Reference Example 10 in N,N-dimethylformamide (30 mL) was added N-chlorosuccinimide (0.95 g, 7.1 mmol), and the mixture was heated to 40° C. After stirring overnight, water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure and directly used for the next reaction.

¹H-NMR (CDCl₃) δ 1.07 (t, J=7.0 Hz, 3H), 3.39 (q, J=7.0 Hz, 2H), 3.76 (t, J=5.1 Hz, 2H), 4.72 (t, J=5.1 Hz, 2H), 8.01-8.02 (m, 2H), 10.09 (s, 1H).

Reference Example 31

The object product was obtained in the same manner as in Reference Example 11 from the compound obtained in Reference Example 30.

¹H-NMR (CDCl₃) δ 1.05 (t, J=7.0 Hz, 3H), 3.38 (q, J=7.0 Hz, 2H), 3.77 (t, J=5.1 Hz, 2H), 4.76 (t, J=5.1 Hz, 2H), 7.12-7.20 (m, 3H), 7.40-7.46 (m, 2H), 8.02 (s, 1H), 10.12 (s, 1H).

Example 92 N²-{[5-chloro-1-(2-ethoxyethyl)-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 1 from the compound obtained in Reference Example 31.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.41 (t, J=7.0 Hz, 3H), 3.32-3.42 (m, 3H), 3.71 (t, J=5.1 Hz, 2H), 4.05 (d, J=14.6 Hz, 1H), 4.14 (d, J=14.6 Hz, 1H), 4.23-4.38 (m, 2H), 5.39 (brs, 1H), 7.11-7.17 (m, 3H), 7.21 (brs, 1H), 7.41-7.45 (m, 2H), 7.83 (s, 1H).

Examples 93-108

The compounds of Examples 93-108 shown in Tables 14-16 were prepared according to the methods described in the above-mentioned Reference Examples and Examples or methods analogous thereto.

TABLE 14 Example structural formula ¹H-NMR (CDCl₃) δ 93

1.11 (t, J = 7.0 Hz, 3H), 1.43 (d, J = 7.0 Hz, 3H), 3.32- 3.45 (m, 3H), 3.82 (t, J = 5.1 Hz, 2H), 4.07 (d, J = 14.9 Hz, 1H), 4.17 (d, J = 14.9 Hz, 1H), 4.65-4.68 (m, 2H), 5.35 (brs, 1H), 6.87- 7.04 (m, 6H), 7.58 (d, J = 8.8 Hz, 1H). 94

1.09 (t, J = 7.0 Hz, 3H), 1.24 (d, J = 7.0 Hz, 6H), 1.41 (d, J = 7.0 Hz, 3H), 2.90 (m, 1H), 3.31-3.40 (m, 3H), 3.68 (t, J = 5.1 Hz, 2H), 4.04 (d, J = 14.9 Hz, 1H), 4.11 (d, J = 14.9 Hz, 1H), 4.20-4.29 (m, 2H), 5.33 (brs, 1H), 6.90-6.99 (m, 4H), 7.16- 7.19 (m, 2H), 7.26 (brs, 1H), 7.66 (m, 1H). 95

1.09 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 2.06- 2.13 (m, 2H), 2.85-2.90 (m, 4H), 3.31-3.40 (m, 3H), 3.68 (t, J = 5.1 Hz, 2H), 4.03 (d, J = 14.6 Hz, 1H), 4.11 (d, J = 14.6 Hz, 1H), 4.18-4.30 (m, 2H), 5.33 (brs, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.86 (m, 1H), 6.97-6.99 (m, 3H), 7.15 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 9.3 Hz, 1H). 96

1.38 (t, J = 7.1 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.32 (q, J = 7.0 Hz, 1H), 3.99 (d, J = 14.8 Hz, 1H), 4.06 (d, J = 14.8 Hz, 1H), 4.06-4.16 (m, 2H), 5.50 (br, 1H), 6.88-7.00 (m, 4H), 7.09-7.16 (m, 3H), 7.65 (m, 1H). 97

1.40 (t, J = 7.3 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.32 (q, J = 7.0 Hz, 1H), 4.00 (d, J = 15.0 Hz, 1H), 4.08 (d, J = 15.0 Hz, 1H), 4.09-4.20 (m, 2H), 5.52 (br, 1H), 6.71 (m, 1H), 6.80 (m, 1H), 6.87-7.15 (m, 4H), 7.69 (d, J = 8.6 Hz, 1H).

TABLE 15 Example structural formula ¹H-NMR (CDCl₃) δ  98

1.39 (t, J = 7.1 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 3.31 (q, J = 6.8 Hz, 1H), 3.99 (d, J = 14.8 Hz, 1H), 4.06 (d, J = 14.8 Hz, 1H), 4.07-4.17 (m, 2H), 5.48 (br, 1H), 6.80-7.12 (m, 6H), 7.65 (m, 1H).  99

0.95-1.05 (m, 2H), 1.13-1.23 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H), 3.18 (m, 1H), 3.30 (q, J = 7.0 Hz, 1H), 4.08 (d, J = 14.4 Hz, 1H) , 4.17 (d, J = 14.4 Hz, 1H), 5.52 (br, 1H), 6.80-7.06 (m, 4H), 7.13 (d, J = 2.4 Hz, 1H), 7.23 (br, 1H), 7.61 (d, J = 8.6 Hz, 1H). 100

0.98-1.08 (m, 2H), 1.15-1.25 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H), 3.19 (m, 1H), 3.36 (q, J = 6.8 Hz, 1H), 4.10 (d, J = 15.4 Hz, 1H), 4.18 (d, J = 15.4 Hz, 1H), 5.44 (br, 1H), 6.93-7.00 (m, 3H), 7.14-7.26 (m, 4H), 7.66 (d, J = 8.6 Hz, 1H). 101

1.20 (s, 3H), 1.29 (s, 3H), 1.32 (d, J = 6.9 Hz, 3H), 2.33 (s, 3H), 3.34 (q, J = 6.9 Hz, 1H), 4.03 (d, J = 13.9 Hz, 1H), 4.07-4.14 (m, 3H), 5.91 (brs, 1H), 6.84-6.91 (m, 2H), 6.94-6.99 (m, 2H), 7.08- 7.15 (m, 3H), 7.61 (m, 1H). 102

1.06 (t, J = 7.0 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H), 2.61 (q, J = 7.6 Hz, 2H), 3.30- 3.38 (m, 3H), 3.65 (t, J = 5.1 Hz, 2H), 4.03 (d, J = 14.6 Hz, 1H), 4.09 (d, J = 14.6 Hz, 1H), 4.16-4.28 (m, 2H), 5.41 (brs, 1H), 6.89-6.96 (m, 4H), 7.11-7.13 (m, 2H), 7.21 (brs, 1H), 7.62 (m, 1H).

TABLE 16 Example structural formula ¹H-NMR (CDCl₃) δ 103

(CD₃OD) 1.24 (s, 3H), 1.25 (s, 3H), 1.61 (d, J = 7.1 Hz, 3H), 4.14 (q, J = 7.1 Hz, 1H), 4.27 (d, J = 15.3 Hz, 1H), 4.32 (d, J = 15.3 Hz, 1H), 4.62 (d, J = 15.1 Hz, 1H), 4.67 (d, J = 15.1 Hz, 1H), 7.00-7.10 (m, 3H), 7.22- 7.28 (m, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H). 104

1.39 (t, J = 7.0 Hz, 3H), 1.43 (d, J = 7.0 Hz, 3H), 3.33 (q, J = 7.0 Hz, 1H), 4.00 (d, J = 14.9 Hz, 1H), 4.03 (d, J = 14.9 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H), 5.63 (brs, 1H), 6.94-7.03 (m, 4H), 7.09 (brs, 1H), 7.12-7.21 (m, 2H), 7.69 (d, J = 8.6 Hz, 1H). 105

(CD₃OD) 1.20 (s, 3H), 1.22 (s, 3H), 1.30 (d, J = 6.8 Hz, 3H), 3.25-3.36 (m, 1H), 4.03 (d, J = 14.3 Hz, 1H), 4.11 (d, J = 14.3 Hz, 1H), 4.18 (d, J = 15.0 Hz, 1H), 4.25 (d, J = 15.0 Hz, 1H), 6.87-6.96 (m, 2H), 7.03-7.18 (m, 3H), 7.57 (d, J = 8.8 Hz, 1H). 106

1.08 (t, J = 7.1 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H), 3.17-3.84 (m, 9H), 3.91- 4.35 (m, 5H), 4.45 (m, 1H), 6.73-7.07 (m, 7H), 7.61 (t, J = 8.6 Hz, 1H). 107

1.08 (t, J = 7.0 Hz, 3H), 1.23- 1.32 (m, 3H), 2.82-4.54 (m, 16H), 6.88-7.08 (m, 6H), 7.63 (m, 1H). 108

1.08 (t, J = 7.0 Hz, 3H), 1.13- 1.23 (m, 3H), 2.28 (m, 1H), 2.57-3.46 (m, 6H), 3.58-4.61 (m, 9H), 6.90-7.06 (m, 6H), 7.61 (m, 1H).

Reference Example 32

The object product was obtained in the same manner as in Reference Example 1 from 4-bromo-2,5-difluoronitrobenzene. ¹H-NMR (CDCl₃) δ 1.23 (t, J=7.0 Hz, 3H), 3.43 (q, J=5.2 Hz, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.70 (t, J=5.2 Hz, 2H), 7.11 (d, J=5.9 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H).

Reference Example 33

The object product was obtained in the same manner as in Reference Example 3-2 from the compound obtained in Reference Example 32.

¹H-NMR (CDCl₃) δ 1.21 (t, J=7.3 Hz, 3H), 3.51-3.58 (m, 4H), 3.65 (t, J=5.1 Hz, 2H), 6.49 (d, J=9.5 Hz, 1H), 6.72 (d, J=6.6 Hz, 1H).

Reference Example 34

The object product was obtained in the same manner as in Reference Example 4 from the compound obtained in Reference Example 33.

¹H-NMR (CDCl₃) δ 1.12 (t, J=7.0 Hz, 3H), 3.43 (q, J=7.0 Hz, 2H), 3.75 (t, J=5.0 Hz, 2H), 4.38 (t, J=5.0 Hz, 2H), 4.88 (s, 2H), 7.45 (d, J=8.8 Hz, 1H), 7.53 (d, J=5.9 Hz, 1H).

Reference Example 35

The object product was obtained in the same manner as in Reference Example 5 from the compound obtained in Reference Example 34.

¹H-NMR (CDCl₃) δ 1.07 (t, J=7.0 Hz, 3H), 3.40 (q, J=7.0 Hz, 2H), 3.76 (t, J=5.0 Hz, 2H), 4.73 (t, J=5.0 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.87 (d, J=6.1 Hz, 1H), 10.09 (s, 1H).

Reference Example 36

The object product was obtained in the same manner as in Reference Example 11 from the compound obtained in Reference Example 35.

¹H-NMR (CDCl₃) δ 1.06 (t, J=7.0 Hz, 3H), 3.40 (q, J=7.0 Hz, 2H), 3.78 (t, J=5.1 Hz, 2H), 4.78 (t, J=5.1 Hz, 2H), 7.15-7.27 (m, 2H), 7.54-7.66 (m, 4H), 10.11 (s, 1H).

Example 109 N²-{[1-(2-ethoxyethyl)-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 36 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.40 (d, J=7.0 Hz, 3H), 3.31-3.41 (m, 3H), 3.72 (t, J=5.0 Hz, 2H), 4.04 (d, J=14.8 Hz, 1H), 4.12 (d, J=14.8 Hz, 1H), 4.26-4.38 (m, 2H), 5.82 (brs, 1H), 7.11-7.15 (m, 2H), 7.22 (brs, 1H), 7.27 (d, J=6.6 Hz, 1H), 7.47 (d, J=10.7 Hz, 1H), 7.49-7.53 (m, 2H).

Reference Example 37

The object product was obtained in the same manner as in Reference Examples 9-11 from 4-bromo-2-fluoronitrobenzene, ethylamine and 4-fluorophenylboranic acid.

¹H-NMR (CDCl₃) δ 1.49 (t, J=7.2 Hz, 3H), 4.71 (q, J=7.2 Hz, 2H), 7.18 (t, J=8.5 Hz, 2H), 7.58-7.64 (m, 4H), 7.98 (d, J=9.3 Hz, 1H), 10.12 (s, 1H).

Example 110 N²-{[1-ethyl-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 37 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.42-1.48 (m, 6H), 3.32 (q, J=7.0 Hz, 1H), 4.03 (d, J=14.8 Hz, 1H), 4.11 (d, J=14.8 Hz, 1H), 4.24 (q, J=7.0 Hz, 2H), 5.60 (brs, 1H), 7.12-7.18 (m, 3H), 7.43-7.46 (m, 2H), 7.57-7.62 (m, 2H), 7.77 (m, 1H).

Reference Example 38

The object product was obtained in the same manner as in Reference Example 37 from 4-bromo-2,5-difluoronitrobenzene.

¹H-NMR (CDCl₃) δ 1.48 (t, J=7.2 Hz, 3H), 4.68 (q, J=7.2 Hz, 2H), 7.14-7.20 (m, 2H), 7.46 (d, J=6.6 Hz, 1H), 7.53-7.59 (m, 2H), 7.67 (d, J=10.5 Hz, 1H), 10.11 (s, 1H).

Example 111 N²-{[1-ethyl-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 38 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.42-1.46 (m, 6H), 3.31 (q, J=7.0 Hz, 1H), 4.01 (d, J=14.6 Hz, 1H), 4.08 (d, J=14.6 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 5.41 (brs, 1H), 7.04 (brs, 1H), 7.13-7.18 (m, 2H), 7.28 (d, J=6.6 Hz, 1H), 7.49 (d, J=11.0 Hz, 1H), 7.52-7.55 (m, 2H).

Reference Example 39

To a solution of 2-chloro-6-fluoroaniline (2.5 g, 17.2 mmol) in chloroform (40 mL) was added bromine (2.75 g, 17.2 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into aqueous sodium thiosulfate solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (hexane:ethyl acetate=9:1-3:1) to give the object product (3.21 g, 83%).

¹H-NMR (CDCl₃) δ 7.07 (dd, J=10.0, 2.0 Hz, 1H), 7.19 (t, J=2.0 Hz, 1H).

Reference Example 40

A solution of sodium peroxoborate tetrahydrate (11.0 g, 71.5 mmol) in acetic acid (50 mL) was heated to 55° C., and a solution of the compound (3.21 g, 14.3 mmol) obtained in Reference Example 39 in acetic acid (30 mL) was added dropwise over 1 hr. After stirring for 3 hr, the mixture was allowed to cool to room temperature and insoluble material was filtered off. The filtrate was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (hexane:ethyl acetate=90:10-5:1) to give the object product (1.30 g, 36%).

¹H-NMR (CDCl₃) δ 7.39 (dd, J=8.3, 2.0 Hz, 1H), 7.50 (t, J=2.0 Hz, 1H).

Reference Example 41

The object product was obtained in the same manner as in Reference Examples 9-11 from the compound obtained in Reference Example 40 and 4-fluorophenylboronic acid.

¹H-NMR (CDCl₃) δ 1.04 (t, J=7.0 Hz, 3H), 3.38 (q, J=7.0 Hz, 2H), 3.79 (t, J=5.1 Hz, 2H), 4.79 (t, J=5.1 Hz, 2H), 7.12-7.18 (m, 2H), 7.51-7.62 (m, 4H), 10.12 (s, 1H).

Example 112 N²-{[4-chloro-1-(2-ethoxyethyl)-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 41 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.40 (d, J=7.0 Hz, 3H), 3.30-3.41 (m, 3H), 3.74 (t, J=5.0 Hz, 2H), 4.07 (d, J=14.8 Hz, 1H), 4.15 (d, J=14.8 Hz, 1H), 4.30-4.44 (m, 2H), 5.65 (brs, 1H), 7.11-7.16 (m, 2H), 7.27 (brs, 1H), 7.35 (d, J=1.4 Hz, 1H), 7.46 (d, J=1.4 Hz, 1H), 7.53-7.57 (m, 2H).

Reference Example 42

The object product was obtained in the same manner as in Reference Example 40 from 4-bromo-2-fluoro-5-methylaniline.

¹H-NMR (CDCl₃) δ 2.43 (s, 3H), 7.48 (d, J=10.0 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H).

Reference Example 43

The object product was obtained in the same manner as in Reference Example 41 from the compound obtained in Reference Example 42.

¹H-NMR (CDCl₃) δ 1.05 (t, J=7.0 Hz, 3H), 2.34 (s, 3H), 3.40 (q, J=7.0 Hz, 2H), 3.77 (t, J=5.4 Hz, 2H), 4.75 (t, J=5.4 Hz, 2H), 7.11-7.16 (m, 2H), 7.29-7.33 (m, 2H), 7.40 (s, 1H), 7.70 (s, 1H), 10.10 (s, 1H).

Example 113 N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenyl)-5-methyl-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 43 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H), 2.33 (s, 3H), 3.30-3.42 (m, 3H), 3.71 (t, J=5.0 Hz, 2H), 4.05 (d, J=14.8 Hz, 1H), 4.13 (d, J=14.8 Hz, 1H), 4.22-4.38 (m, 2H), 5.43 (brs, 1H), 7.09-7.14 (m, 3H), 7.29-7.34 (m, 3H), 7.61 (s, 1H).

Reference Example 44

The object product was obtained in the same manner as in Reference Example 40 from 4-bromo-2,6-difluoroaniline.

¹H-NMR (CDCl₃) δ 7.28-7.32 (m, 2H).

Reference Example 45

The object product was obtained in the same manner as in Reference Example 41 from the compound obtained in Reference Example 44.

¹H-NMR (CDCl₃) δ 1.06 (t, J=7.0 Hz, 3H), 3.41 (q, J=7.0 Hz, 2H), 3.81 (t, J=5.3 Hz, 2H), 4.81 (t, J=5.3 Hz, 2H), 7.15-7.19 (m, 2H), 7.27 (dd, J=11.0, 1.6 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.57-7.61 (m, 2H), 10.16 (s, 1H).

Example 114 N²-{[1-(2-ethoxyethyl)-4-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 45 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.11 (t, J=7.0 Hz, 3H), 1.42 (d, J=6.8 Hz, 3H), 3.32-3.45 (m, 3H), 3.77 (t, J=5.0 Hz, 2H), 4.08 (d, J=14.6 Hz, 1H), 4.18 (d, J=14.6 Hz, 1H), 4.31-4.46 (m, 2H), 6.00 (brs, 1H), 7.12-7.29 (m, 5H), 7.52-7.59 (m, 2H).

Reference Example 46

The object product was obtained in the same manner as in Reference Example 40 from 4-bromo-6-fluoro-3-trifluoromethylaniline.

Reference Example 47

The object product was obtained in the same manner as in Reference Example 41 from the compound obtained in Reference Example 46.

¹H-NMR (CDCl₃) δ 1.03 (t, J=7.0 Hz, 3H), 3.38 (q, J=7.0 Hz, 2H), 3.77 (t, J=5.1 Hz, 2H), 4.78 (t, J=5.1 Hz, 2H), 7.09-7.13 (m, 2H), 7.31-7.35 (m, 2H), 7.53 (s, 1H), 8.32 (s, 1H), 10.16 (s, 1H).

Example 115 N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 47 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.09 (t, J=7.0 Hz, 3H), 1.43 (d, J=7.0 Hz, 3H), 3.31-3.42 (m, 3H), 3.71 (t, J=5.0 Hz, 2H), 4.09 (d, J=15.0 Hz, 1H), 4.18 (d, J=15.0 Hz, 1H), 4.27-4.38 (m, 2H), 5.34 (brs, 1H), 7.10 (t, J=8.7 Hz, 2H), 7.13 (brs, 1H), 7.25 (s, 1H), 7.31-7.36 (m, 2H), 8.13 (s, 1H).

Reference Example 48

The object product was obtained in the same manner as in Reference Examples 1, 3, 4 and 11 from 2,5-difluoro-4-bromonitrobenzene, 4-aminotetrahydropyran hydrochloride and 4-fluorophenylboronic acid.

¹H-NMR (CDCl₃) δ 1.94 (m, 2H), 2.58 (m, 2H), 3.62 (m, 2H), 4.20 (m, 2H), 4.69 (m, 1H), 4.92 (s, 2H), 7.12-7.21 (m, 2H), 7.45 (d, 1H, J=10.6 Hz), 7.48-7.57 (m, 3H).

Reference Example 49

To a solution of the compound (0.82 g, 2.38 mmol) obtained in Reference Example 48 in dichloromethane (20 mL) were added diisopropylethylamine (2.12 ml, 11.9 mmol) and thionyl chloride (1 mol/L dichloromethane solution, 11.9 ml, 11.9 mmol). After heating under reflux for 1 hr, the mixture was cooled to 0° C. and water was added thereto. The mixture was neutralized with 2 mol/L aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the obtained residue was directly used for the next reaction.

¹H-NMR (CDCl₃) δ 1.96-2.05 (m, 2H), 2.55-2.70 (m, 2H), 3.58-3.66 (m, 2H), 4.19-4.24 (m, 2H), 4.61 (m, 1H), 4.88 (s, 2H), 7.15-7.22 (m, 2H), 7.50-7.57 (m, 4H).

Example 116 N²-{[5-fluoro-6-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

To a solution of the compound (0.16 g, 0.44 mmol) obtained in Reference Example 49 in tetrahydrofuran (5 mL) were added N-(2,4-dimethoxybenzyl)alaninamide (0.12 g, 0.49 mmol), diisopropylethylamine (0.12 ml, 0.66 mmol) and sodium iodide (0.07 g, 0.44 mmol). After heating under reflux for 2 hr, the mixture was allowed to cool to room temperature and water was added thereto. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To the residue was added trifluoroacetic acid (2 mL) and the mixture was heated to 50° C. After stirring for 1 hr, the mixture was cooled to 0° C., chloroform was added thereto, and the mixture was neutralized with 2 mol/L aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (chloroform:methanol=99:1-85:15) and recrystallized from ethyl acetate-hexane to give the object product (0.09 mg, 50%). ¹H-NMR (CDCl₃) δ 1.40 (d, J=7.0 Hz, 3H), 1.86-1.89 (m, 2H), 2.49-2.64 (m, 2H), 3.32 (m, 1H), 3.53-3.61 (m, 2H), 4.11-4.20 (m, 4H), 4.53 (m, 1H), 5.43 (brs, 1H), 7.08 (brs, 1H), 7.12-7.18 (m, 2H), 7.43-7.52 (m, 4H).

Reference Example 50

The object product was obtained in the same manner as in Reference Examples 1-3 from 2,4-difluoronitrobenzene, 2-aminoethanol and 4-fluorophenol.

¹H-NMR (CDCl₃) δ 3.23 (t, J=4.8 Hz, 2H), 3.84 (t, J=4.8 Hz, 2H), 6.28 (d, J=7.8 Hz, 1H), 6.37 (d, J=2.4 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.27-6.98 (m, 4H).

Reference Example 51

To a solution of the compound (2.7 g, 10.5 mmol) obtained in Reference Example 50 in N,N-dimethylformamide (50 mL) were added t-butyl-diphenylsilyl chloride (3.6 ml, 12.6 mmol) and imidazole (1.1 g, 15.8 mmol), and the mixture was stirred at room temperature. After stirring for 1 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure, and the obtained residue was directly used for the next reaction.

¹H-NMR (CDCl₃) δ 1.05 (s, 9H), 3.16 (t, J=5.1 Hz, 2H), 3.87 (t, J=5.1 Hz, 2H), 6.24-6.28 (m, 2H), 6.65 (d, J=8.1 Hz, 1H), 6.82-6.94 (m, 4H), 7.31-7.43 (m, 6H), 7.62-7.72 (m, 4H).

Reference Example 52

The object product was obtained in the same manner as in Reference Examples 4 and 5 and Example 2 from the compound obtained in Reference Example 51 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.02 (s, 9H), 1.45 (d, J=6.8 Hz, 3H), 3.34 (q, J=6.8 Hz, 1H), 3.95 (t, J=5.4 Hz, 2H), 4.09 (d, J=14.9 Hz, 1H), 4.14 (d, J=14.9 Hz, 1H), 4.23-4.36 (m, 2H), 6.08 (brs, 1H), 6.87-6.93 (m, 3H), 7.00-7.05 (m, 3H), 7.18 (brs, 1H), 7.30-7.36 (m, 4H), 7.41-7.47 (m, 6H), 7.79 (d, J=8.8 Hz, 1H).

Example 117 N²-{[6-(4-fluorophenoxy)-1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

To a solution (4 mL) of the compound (1.2 g, 2.0 mmol) obtained in Reference Example 52 in THF was added tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 3.0 ml, 3.0 mmol), and the mixture was stirred at room temperature. After stirring for 1 hr, water was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (chloroform:methanol=99:1-85:15) and recrystallized from chloroform-hexane to give the object product (300 mg, 40%).

¹H-NMR (CDCl₃) δ 1.32 (d, J=7.0 Hz, 3H), 3.33 (q, J=7.0 Hz, 1H), 3.92-3.98 (m, 2H), 4.03 (d, J=13.6 Hz, 1H), 4.08 (d, J=13.6 Hz, 1H), 4.30 (t, J=4.6 Hz, 2H), 5.50 (brs, 1H), 6.78 (brs, 1H), 6.92-7.03 (m, 6H), 7.64 (d, J=8.8 Hz, 1H).

Reference Example 53

To a solution of the compound (1.0 g, 4.4 mmol) obtained in Reference Example 1 in N,N-dimethylformamide (44 mL) was added N-chlorosuccinimide (0.64 g, 4.8 mmol), and the mixture was heated to 40° C. After stirring overnight, the mixture was allowed to cool to room temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane:ethyl acetate=95:5-90:10-75:25-50:50) to give the object product (0.82 g, 72%).

¹H-NMR (CDCl₃) δ 1.22 (t, J=7.0 Hz, 3H), 3.41 (q, J=5.2 Hz, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.69 (t, J=5.2 Hz, 2H), 6.62 (d, J=11.5 Hz, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.31 (brs, 1H).

Reference Example 54

The object product was obtained in the same manner as in Reference Examples 2-5 from the compound obtained in Reference Example 53.

¹H-NMR (CDCl₃) δ 0.95 (t, J=7.0 Hz, 3H), 3.29 (q, J=7.0 Hz, 2H), 3.67 (t, J=5.0 Hz, 2H), 4.59 (t, J=5.0 Hz, 2H), 6.96-7.10 (m, 5H), 7.98 (s, 1H), 10.02 (s, 1H).

Example 118 N²-{[5-chloro-1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide

The object product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 54 and (L)-alaninamide hydrochloride.

¹H-NMR (CDCl₃) δ 1.05 (t, J=7.0 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H), 3.29-3.38 (m, 3H), 3.63 (t, J=5.0 Hz, 2H), 4.01 (d, J=14.8 Hz, 1H), 4.10 (d, J=14.8 Hz, 1H), 4.15-4.28 (m, 2H), 5.68 (brs, 1H), 6.87-6.91 (m, 2H), 6.97-7.02 (m, 3H), 7.16 (brs, 1H), 7.80 (s, 1H).

Examples 119-190

The compounds of Examples 119-190 shown in Tables 17-31 were prepared according to the methods described in the above-mentioned Reference Examples and Examples or methods analogous thereto.

TABLE 17 Example structural formula ¹H-NMR (CDCl₃) δ 119

1.40 (d, J = 7.0 Hz, 3H), 1.55 (m, 1H), 1.80-1.95 (m, 2H), 2.03 (m, 1H), 2.33 (s, 3H), 3.32 (q, J = 7.0 Hz, 1H), 3.70 (m, 1H), 3.80 (m, 1H), 4.01- 4.21 (m, 5H), 5.57 (brs, 1H), 6.87-7.01 (m, 4H), 7.12 (d, J = 8.3 Hz, 2H), 7.27 (brs, 1H), 7.65 (d, J = 8.3 Hz, 1H). 120

1.41 (d, J = 7.0 Hz, 3H), 1.57 (m, 1H), 1.84-1.95 (m, 2H), 2.05 (m, 1H), 3.32 (q, J = 7.0 Hz, 1H), 3.71 (m, 1H), 3.80 (m, 1H), 4.03-4.25 (m, 5H), 5.61 (brs, 1H), 6.94-7.00 (m, 3H), 7.03 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.23 (brs, 1H), 7.69 (d, J = 8.4 Hz, 1H). 121

1.41 (d, J = 7.0 Hz, 3H), 1.57 (m, 1H), 1.80-2.10 (m, 3H), 3.31 (q, J = 7.0 Hz, 1H), 3.66- 3.84 (m, 2H), 4.00-4.24 (m, 5H), 5.40 (br, 1H), 6.78-7.05 (m, 5H), 7.24 (br, 1H), 7.65 (d, J = 8.6 Hz, 1H). 122

1.43 (d, J = 7.0 Hz, 3H), 2.03 (m, 2H), 3.28-3.38 (m, 6H), 4.02 (d, J = 14.7 Hz, 1H), 4.08 (d, J = 14.7 Hz, 1H), 4.21 (t, J = 6.8 Hz, 2H), 5.47 (br, 1H), 6.66-6.84 (m, 2H), 6.96 (dd, J = 8.6, 2.2 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.10 (m, 1H), 7.20 (br, 1H), 7.69 (d, J = 8.8 Hz, 1H). 123

1.42 (d, J = 7.0 Hz, 3H), 2.02 (m, 2H), 3.25-3.36 (m, 6H), 4.00 (d, J = 14.7 Hz, 1H), 4.06 (d, J = 14.7 Hz, 1H), 4.19 (t, J = 6.8 Hz, 2H), 5.55 (br, 1H), 6.79-7.06 (m, 5H), 7.21 (br, 1H), 7,.64 (d, J = 8.6 Hz, 1H).

TABLE 18 Example structural formula ¹H-NMR (CDCl₃) δ 124

1.41 (d, J = 6.8 Hz, 3H), 1.55 (m, 1H), 1.75-2.10 (m, 3H), 3.35 (q, J = 6.8 Hz, 1H), 3.66-3.84 (m, 2H), 4.00-4.30 (m, 5H), 5.45 (br, 1H), 6.70 (m, 1H), 6.80 (m, 1H), 6.95 (dd, J = 8.6, 2.2 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 7.09 (m, 1H), 7.21 (br, 1H), 7.68 (d, J = 8.6 Hz, 1H). 125

1.40 (d, J = 7.0 Hz, 3H), 1.55 (m, 1H), 1.80-2.10 (m, 3H), 3.34 (q, J = 7.0 Hz, 1H), 3.66-3.83 (m, 2H), 3.98-4.28 (m, 5H), 5.44 (br, 1H), 6.79- 7.05 (m, 5H), 7.22 (br, 1H), 7.64 (d, J = 8.6 Hz, 1H). 126

1.42 (d, J = 7.0 Hz, 3H), 2.01 (m, 2H), 2.33 (s, 3H), 3.28 (s, 3H), 3.28 (m, 2H), 3.33 (q, J = 7.0 Hz, 1H), 4.00 (d, J = 14.7 Hz, 1H), 4.07 (d, J = 14.7 Hz, 1H), 4.18 (t, J = 6.8 Hz, 2H), 5.50 (br, 1H), 6.87-7.02 (m, 4H), 7.12 (m, 2H), 7.23 (br, 1H), 7.64 (d, J = 8.6 Hz, 1H). 127

1.42 (d, J = 6.8 Hz, 3H), 2.03 (m, 2H), 3.28 (s, 3H), 3.28- 3.38 (m, 3H), 4.02 (d, J = 14.8 Hz, 1H), 4.08 (d, J = 14.8 Hz, 1H), 4.21 (t, J = 6.9 Hz, 2H), 5.56 (br, 1H), 6.95-7.00 (m, 3H), 7.05 (d, J = 2.2 Hz, 1H), 7.14-7.25 (m, 3H), 7.69 (d, J = 8.8 Hz, 1H). 128

1.40 (d, J = 7.0 Hz, 3H), 1.80- 1.95 (m, 2H), 2.50 (m, 2H), 3.28 (q, J = 7.0 Hz, 1H), 3.56 (m, 2H), 4.00-4.22 (m, 4H), 4.50 (m, 1H), 5.59 (br, 1H), 6.65-6.83 (m, 2H), 6.90 (br, 1H), 6.95 (dd, J = 8.8, 2.2 Hz, 1H), 7.10 (m, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H).

TABLE 19 Example structural formula ¹H-NMR (CDCl₃) δ 129

1.40 (d, J = 6.9 Hz, 3H), 1.78-1.86 (m, 2H), 2.33 (s, 3H), 2.43-2.58 (m, 2H), 3.28 (q, J = 6.9 Hz, 1H), 3.50- 3.59 (m, 2H), 4.00-4.19 (m, 4H), 4.47 (m, 1H), 5.72 (brs, 1H), 6.87-7.00 (m, 4H), 7.10- 7.14 (m, 2H), 7.27 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H). 130

1.40 (d, J = 6.9 Hz, 3H), 1.80-1.91 (m, 2H), 2.44-2.59 (m, 2H), 3.29 (q, J = 6.6 Hz, 1H), 3.50-3.60 (m, 2H), 4.01- 4.21 (m, 4H), 4.50 (m, 1H), 5.86 (brs, 1H), 6.92-7.00 (m, 4H), 7.14-7.20 (m, 2H), 7.31 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H). 131

1.40 (d, J = 6.9 Hz, 3H), 1.55 (m, 1H), 1.78-1.89 (m, 2H), 2.01 (m, 1H), 2.33 (s, 3H), 3.34 (q, J = 6.9 Hz, 1H), 3.71 (m, 1H), 3.79 (m, 1H), 3.98-4.27 (m, 5H), 5.57 (brs, 1H), 6.86-6.91 (m, 2H), 6.93-7.01 (m, 2H), 7.12 (d, J = 8.3 Hz, 2H), 7.27 (brs, 1H), 7.65 (d, J = 8.3 Hz, 1H). 132

1.41 (d, J = 6.9 Hz, 3H), 1.56 (m, 1H), 1.79-1.95 (m, 2H), 2.05 (m, 1H), 3.35 (q, J = 6.9 Hz, 1H), 3.70 (m, 1H), 3.80 (m, 1H), 3.99-4.21 (m, 4H), 4.25 (dd, J = 14.8, 2.8 Hz, 1H), 5.68 (brs, 1H), 6.94-7.00 (m, 3H), 7.03 (d, J = 2.2 Hz, 1H), 7.13-7.19 (m, 2H), 7.22 (brs, 1H), 7.69 (d, J = 8.5 Hz, 1H). 133

1.38 (d, J = 6.8 Hz, 3H), 2.03- 2.09 (m, 2H), 3.36-3.55 (m, 3H), 4.06 (d, J = 14.3 Hz, 1H), 4.13 (d, J = 14.3 Hz, 1H), 4.22- 4.41 (m, 2H), 5.72 (brs, 1H), 6.95-7.18 (m, 7H), 7.68 (d, J = 8.6 Hz, 1H).

TABLE 20 Example structural formula ¹H-NMR (CDCl₃) δ 134

1.32 (d, J = 7.0 Hz, 3H), 3.35 (q, J = 7.0 Hz, 1H), 3.96 (t, J = 4.8 Hz, 2H), 4.04 (d, J = 14.0 Hz, 1H), 4.10 (d, J = 14.0 Hz, 1H), 4.32 (t, J = 4.8 Hz, 2H), 5.65 (brs, 1H), 6.85 (brs, 1H), 6.95-7.00 (m, 4H), 7.15- 7.18 (m, 2H), 7.65 (d, J = 9.4 Hz, 1H). 135

1.38 (t, J = 7.2 Hz, 3H), 1.47 (s, 6H), 2.34 (s, 3H), 3.97 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 5.45 (br, 1H), 6.85-7.00 (m, 4H), 7.13 (m, 2H), 7.32 (br, 1H), 7.65 (d, J = 8.8 Hz, 1H). 136

1.00-1.28 (m, 4H), 1.48 (s, 6H), 3.18 (m, 1H), 4.08 (s, 2H), 5.58 (br, 1H), 6.90-7.05 (m, 5H), 7.15 (d, J = 2.4 Hz, 1H), 7.42 (br, 1H), 7.64 (d, J = 8.8 Hz, 1H). 137

1.46 (s, 6H), 1.57 (m, 1H), 1.80-2.10 (m, 3H), 3.67-3.84 (m, 2H), 3.96-4.25 (m, 5H), 5.33 (br, 1H), 6.82 (m, 1H), 6.89-7.04 (m, 4H), 7.45 (br, 1H), 7.65 (d, J = 8.6 Hz, 1H). 138

1.31 (t, J = 7.3 Hz, 3H), 1.47 (s, 6H), 3.97 (s, 2H), 4.11 (q, J = 7.3 Hz, 2H), 5.59 (br, 1H), 6.92-7.06 (m, 6H), 7.30 (br, 1H), 7.67 (m, 1H).

TABLE 21 Example structural formula ¹H-NMR (CDCl₃) δ 139

1.39 (t, J = 7.1 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 3.32 (q, J = 6.8 Hz, 1H), 3.39 (d, J = 14.8 Hz, 1H), 4.06 (d, J = 14.8 Hz, 1H), 4.12 (m, 2H), 5.50 (br, 1H), 6.92-7.14 (m, 7H), 7.67 (m, 1H). 140

1.47 (s, 6H), 1.78-1.86 (m, 2H), 2.33 (s, 3H), 2.44-2.58 (m, 2H), 3.48-3.58 (m, 2H), 4.00 (s, 2H), 4.12-4.20 (m, 2H), 4.41 (m, 1H), 5.65 (brs, 1H), 6.86-6.91 (m, 2H), 6.94 (dd, J = 8.8, 2.2 Hz, 1H), 7.10-7.14 (m, 2H), 7.17 (brs, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H). 141

1.09 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 3.39 (q, J = 7.0 Hz, 2H), 3.70 (t, J = 5.0 Hz, 2H), 4.03 (s, 2H), 4.26 (t, J = 5.0 Hz, 2H), 5.41 (br, 1H), 6.70 (m, 1H), 6.80 (m, 1H), 6.94-7.15 (m, 3H), 7.46 (br, 1H), 7.70 (d, J = 8.4 Hz, 1H). 142

1.47 (s, 6H), 2.02 (m, 2H), 2.33 (s, 3H), 3.28 (s, 3H), 3.28 (m, 2H), 3.98 (s, 2H), 4.18 (t, J = 6.9 Hz, 2H), 5.48 (br, 1H), 6.87-7.02 (m, 4H), 7.10 (d, J = 8.2 Hz, 2H), 7.44 (br, 1H), 7.65 (d, J = 8.6 Hz, 1H). 143

1.45 (s, 6H), 3.96 (t, J = 4.8 Hz, 2H), 4.01 (s, 2H), 4.30 (t, J = 4.8 Hz, 2H), 5.39 (brs, 1H), 6.92-7.05 (m, 7H), 7.65 (d, J = 8.6 Hz, 1H).

TABLE 22 Example structural formula ¹H-NMR (CDCl₃) δ 144

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.8 Hz, 3H), 2.38 (s, 3H), 3.33-3.43 (m, 3H), 3.74 (t, J = 5.1 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 4.31- 4.43 (m, 2H), 5.89 (brs, 1H), 7.26-7.32 (m, 4H), 7.48-7.55 (m, 3H), 7.76 (d, J = 8.3 Hz, 1H). 145

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.32- 3.42 (m, 3H), 3.76 (t, J = 5.1 Hz, 2H), 4.07 (d, J = 14.8 Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 4.30-4.41 (m, 2H), 5.75 (brs, 1H), 7.25-7.32 (m, 3H), 7.45-7.47 (m, 2H), 7.63- 7.65 (m, 2H), 7.78 (d, J = 9.0 Hz, 1H). 146

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.8 Hz, 3H), 3.32- 3.42 (m, 3H), 3.76 (t, J = 5.0 Hz, 2H), 4.07 (d, J = 14.6 Hz, 1H), 4.16 (d, J = 14.6 Hz, 1H), 4.31-4.43 (m, 2H), 5.70 (brs, 1H), 7.25 (brs, 1H), 7.49-7.52 (m, 2H), 7.68-7.74 (m, 4H), 7.80 (d, J = 8.3 Hz, 1H). 147

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.31- 3.43 (m, 3H), 3.75 (t, J = 5.0 Hz, 2H), 4.08 (d, J = 14.7 Hz, 1H), 4.17 (d, J = 14.7 Hz, 1H), 4.30-4.43 (m, 2H), 5.73 (brs, 1H), 6.90-7.00 (m, 2H), 7.28-7.50 (m, 4H), 7.79 (d, J = 8.4 Hz, 1H). 148

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.34-3.43 (m, 3H), 3.76 (t, J = 5.0 Hz, 2H), 4.08 (d, J = 14.8 Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 4.29- 4.43 (m, 2H), 5.98 (brs, 1H), 7.18-7.44 (m, 6H), 7.77 (d, J = 8.4 Hz, 1H).

TABLE 23 Example structural formula ¹H-NMR (CDCl₃) δ 149

1.11 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 3.40 (q, J = 7.0 Hz, 2H), 3.77 (t, J = 5.0 Hz, 2H), 4.06 (s, 2H), 4.36 (t, J = 5.0 Hz, 2H), 5.47 (brs, 1H), 7.12-7.17 (m, 2H), 7.44-7.46 (m, 2H), 7.51 (brs, 1H), 7.57-7.60 (m, 2H), 7.78 (m, 1H). 150

1.01 (t, J = 7.4 Hz, 3H), 1.10 (t, J = 7.0 Hz, 3H), 1.69-1.87 (m, 2H), 3.16 (t, J = 6.3 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.76 (t, J = 5.0 Hz, 2H), 4.04 (d, J = 14.6 Hz, 1H), 4.16 (d, J = 14.6 Hz, 1H), 4.30-4.45 (m, 2H), 5.96 (brs, 1H), 7.11-7.16 (m, 2H), 7.21 (brs, 1H), 7.43-7.46 (m, 2H), 7.56- 7.60 (m, 2H), 7.77 (m, 1H). 151

1.00 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H), 1.10 (t, J = 7.0 Hz, 3H), 2.08 (m, 1H), 2.98 (d, J = 5.6 Hz, 1H), 3.40 (q, J = 7.0 Hz, 2H), 3.76 (q, J = 5.2 Hz, 2H), 4.02 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 14.4 Hz, 1H), 4.31- 4.49 (m, 2H), 5.66 (brs, 1H), 7.09 (brs, 1H), 7.12-7.17 (m, 2H), 7.44-7.46 (m, 2H), 7.57-7.60 (m, 2H), 7.76 (m, 1H). 152

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.8 Hz, 3H), 2.45 (s, 3H), 3.32-3.42 (m, 3H), 3.76 (t, J = 5.1 Hz, 2H), 4.06 (d, J = 14.8 Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 4.30-4.42 (m, 2H), 5.68 (brs, 1H), 7.16-7.52 (m, 7H), 7.77 (m, 1H). 153

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 2.29 (s, 3H), 3.33- 3.42 (m, 3H), 3.73 (t, J = 5.1 Hz, 2H), 4.08 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.8 Hz, 1H), 4.26- 4.38 (m, 2H), 5.66 (brs, 1H), 7.22- 7.30 (m, 7H), 7.75 (m, 1H).

TABLE 24 Example structural formula ¹H-NMR (CDCl₃) δ 154

1.45 (t, J = 7.0 Hz, 3H), 1.48 (s, 6H), 4.01 (s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 5.82 (brs, 1H), 7.11- 7.17 (m, 2H), 7.34 (brs, 1H), 7.42-7.45 (m, 2H), 7.56-7.61 (m, 2H), 7.77 (m, 1H). 155

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 3.32-3.42 (m, 3H), 3.74 (t, J = 5.1 Hz, 2H), 4.08 (d, J = 14.6 Hz, 1H), 4.16 (d, J = 14.6 Hz, 1H), 4.29-4.41 (m, 2H), 5.41 (brs, 1H), 7.06 (m, 1H), 7.24-7.30 (m, 3H), 7.35-7.39 (m, 2H), 7.77 (d, J = 8.3 Hz, 1H). 156

1.10 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 3.40 (q, J = 7.0 Hz, 2H), 3.75 (t, J = 5.1 Hz, 2H), 4.07 (s, 2H), 4.34 (t, J = 5.1 Hz, 2H), 5.37 (brs, 1H), 7.06 (m, 1H), 7.24-7.39 (m, 5H), 7.77 (d, J = 8.3 Hz, 1H). 157

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 2.27 (s, 3H), 3.33-3.42 (m, 3H), 3.73 (t, J = 5.4 Hz, 2H), 4.08 (d, J = 15.4 Hz, 1H), 4.15 (d, J = 15.4 Hz, 1H), 4.27-4.40 (m, 2H), 5.35 (brs, 1H), 6.92-7.01 (m, 2H), 7.17-7.25 (m, 3H), 7.29 (brs, 1H), 7.34 (d, J = 8.3 Hz, 1H). 158

1.11 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 2.26 (s, 3H), 3.40 (q, J = 7.0 Hz, 2H), 3.74 (t, J = 5.0 Hz, 2H), 4.07 (s, 2H), 4.33 (t, J = 5.0 Hz, 2H), 5.47 (brs, 1H), 6.92- 7.01 (m, 2H), 7.17-7.27 (m, 3H), 7.54 (brs, 1H), 7.75 (d, J = 8.3 Hz, 1H).

TABLE 25 Example structural formula ¹H-NMR (CDCl₃) δ 159

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 3.32-3.42 (m, 3H), 3.72 (t, J = 5.1 Hz, 2H), 4.07 (d, J = 14.6 Hz, 1H), 4.15 (d, J = 14.6 Hz, 1H), 4.26-4.38 (m, 2H), 5.81 (brs, 1H), 7.07-7.27 (m, 5H), 7.33 (brs, 1H), 7.73 (d, J = 8.3 Hz, 1H). 160

1.10 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 2.26 (s, 3H), 2.38 (s, 3H), 3.39 (q, J = 7.0 Hz, 2H), 3.73 (t, J = 5.1 Hz, 2H), 4.06 (s, 2H), 4.32 (t, J = 5.1 Hz, 2H), 5.49 (brs, 1H), 7.06-7.26 (m, 5H), 7.55 (brs, 1H), 7.75 (d, J = 8.3 Hz, 1H). 161

1.11 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 2.32 (s, 3H), 2.36 (s, 3H), 3.31-3.43 (m, 3H), 3.76 (t, J = 5.0 Hz, 2H), 4.07 (d, J = 14.9 Hz, 1H), 4.16 (d, J = 14.9 Hz, 1H), 4.29-4.44 (m, 2H), 5.36 (brs, 1H), 7.23 (m, 1H), 7.36 (brs, 1H), 7.30-7.51 (m, 4H), 7.76 (d, J = 9.0 Hz, 1H). 162

1.10 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 2.32 (s, 3H), 2.36 (s, 3H), 3.39 (q, J = 7.0 Hz, 2H), 3.77 (t, J = 5.0 Hz, 2H), 4.06 (s, 2H), 4.36 (t, J = 5.0 Hz, 2H), 5.28 (brs, 1H), 7.22 (m, 1H), 7.37-7.51 (m, 4H), 7.55 (brs, 1H), 7.77 (d, J = 8.6 Hz, 1H). 163

1.01 (t, J = 7.5 Hz, 3H), 1.10 (t, J = 7.0 Hz, 3H), 1.65-1.85 (m, 2H), 2.32 (s, 3H), 2.36 (s, 3H), 3.16 (t, J = 6.3 Hz, 1H), 3.39 (q, J = 7.0 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H), 4.05 (d, J = 14.7 Hz, 1H), 4.16 (d, J = 14.7 Hz, 1H), 4.29-4.46 (m, 2H), 5.42 (brs, 1H), 7.22 (m, 2H), 7.36-7.52 (m, 4H), 7.76 (d, J = 9.0 Hz, 1H).

TABLE 26 Example structural formula ¹H-NMR (CDCl₃) δ 164

1.09 (t, J = 7.0 Hz, 3H), 1.43 (d, J = 7.1 Hz, 3H), 2.01 (s, 6H), 2.35 (s, 3H), 3.33-3.41 (m, 3H), 3.76 (t, J = 5.0 Hz, 2H), 4.07 (d, J = 14.8 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H), 4.24-4.36 (m, 2H), 5.37 (brs, 1H), 6.97 (s, 2H), 7.04 (dd, J = 8.0, 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.32 (brs, 1H), 7.76 (d, J = 8.0 Hz, 1H). 165

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 2.41 (s, 3H), 3.31-3.43 (m, 3H), 3.75 (t, J = 5.1 Hz, 2H), 4.07 (d, J = 14.7 Hz, 1H), 4.16 (d, J = 14.7 Hz, 1H), 4.28-4.42 (m, 2H), 5.33 (brs, 1H), 6.98-7.06 (m, 2H), 7.27 (brs, 1H), 7.35-7.49 (m, 3H), 7.78 (d, J = 8.4 Hz, 1H). 166

1.10 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 2.41 (s, 3H), 3.39 (q, J = 7.0 Hz, 2H), 3.76 (t, J = 5.1 Hz, 2H), 4.07 (s, 2H), 4.35 (t, J = 5.1 Hz, 2H), 5.31 (brs, 1H), 6.96-7.05 (m, 2H), 7.35-7.49 (m, 3H), 7.52 (brs, 1H), 7.78 (d, J = 8.4 Hz, 1H). 167

1.11 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 2.36 (s, 3H), 3.31-3.44 (m, 3H), 3.76 (t, J = 5.2 Hz, 2H), 4.07 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.8 Hz, 1H), 4.28-4.44 (m, 2H), 5.37 (brs, 1H), 7.08 (t, J = 8.9 Hz, 1H), 7.37-7.46 (m, 5H), 7.77 (d, J = 9.0 Hz, 1H). 168

1.11 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 2.36 (s, 3H), 3.40 (q, J = 7.0 Hz, 2H), 3.77 (t, J = 5.0 Hz, 2H), 4.06 (s, 2H), 4.36 (t, J = 5.0 Hz, 2H), 5.30 (brs, 1H), 7.08 (t, J = 8.8 Hz, 1H), 7.36- 7.46 (m, 4H), 7.51 (brs, 1H), 7.77 (d, J = 8.1 Hz, 1H).

TABLE 27 Example structural formula ¹H-NMR (CDCl₃) δ 169

1.11 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 2.33 (s, 3H), 3.31-3.44 (m, 3H), 3.76 (t, J = 5.0 Hz, 2H), 4.07 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.8 Hz, 1H), 4.29- 4.44 (m, 2H), 5.42 (brs, 1H), 7.23-7.33 (m, 4H), 7.42-7.49 (m, 2H), 7.77 (d, J = 8.8 Hz, 1H). 170

1.11 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 2.33 (s, 3H), 3.40 (q, J = 7.0 Hz, 2H), 3.77 (t, J = 5.0 Hz, 2H), 4.07 (s, 2H), 4.36 (t, J = 5.0 Hz, 2H), 5.35 (brs, 1H), 7.22-7.33 (m, 4H), 7.46-7.49 (m, 2H), 7.78 (d, J = 9.0 Hz, 1H). 171

1.09 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 3.34- 3.42 (m, 3H), 3.75 (t, J = 5.1 Hz, 2H), 4.09 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.8 Hz, 1H), 4.29-4.41 (m, 2H), 5.67 (brs, 1H), 7.14-7.16 (m, 2H), 7.23-7.30 (m, 2H), 7.41- 7.52 (m, 2H), 7.80 (d, J = 8.5 Hz, 1H). 172

1.10 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.31- 3.42 (m, 3H), 3.74 (t, J = 5.1 Hz, 2H), 3.81 (s, 3H), 4.07 (d, J = 14.8 Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 4.28- 4.40 (m, 2H), 5.37 (brs, 1H), 6.73-6.78 (m, 2H), 7.28-7.41 (m, 4H), 7.75 (d, J = 8.3 Hz, 1H). 173

1.11 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.32-3.43 (m, 3H), 3.76 (t, J = 5.0 Hz, 2H), 3.98 (s, 3H), 4.08 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.8 Hz, 1H), 4.31-4.43 (m, 2H), 5.40 (brs, 1H), 7.13-7.20 (m, 4H), 7.44-7.46 (m, 2H), 7.78 (d, J = 9.0 Hz, 1H).

TABLE 28 Example structural formula ¹H-NMR (CDCl₃) δ 174

1.11 (t, J = 7.0 Hz, 3H), 1.47 (s, 6H), 3.39 (q, J = 7.0 Hz, 2H), 3.75 (t, J = 5.1 Hz, 2H), 3.81 (s, 3H), 4.06 (s, 2H), 4.33 (t, J = 5.1 Hz, 2H), 5.36 (brs, 1H), 6.72-6.78 (m, 2H), 7.28-7.40 (m, 3H), 7.53 (brs, 1H), 7.75 (d, J = 8.3 Hz, 1H). 175

1.11 (t, J = 7.0 Hz, 3H), 1.48 (s, 6H), 3.39 (q, J = 7.0 Hz, 2H), 3.77 (t, J = 5.1 Hz, 2H), 3.98 (s, 3H), 4.07 (s, 2H), 4.37 (t, J = 5.1 Hz, 2H), 5.29 (brs, 1H), 7.14-7.20 (m, 4H), 7.44-7.51 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H). 176

1.09 (t, J = 7.0 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 3.32- 3.42 (m, 3H), 3.71 (t, J = 5.1 Hz, 2H), 4.05 (d, J = 14.6 Hz, 1H), 4.14 (d, J = 14.6 Hz, 1H), 4.23-4.38 (m, 2H), 5.39 (brs, 1H), 7.11-7.17 (m, 3H), 7.21 (brs, 1H), 7.41- 7.45 (m, 2H), 7.83 (s, 1H). 177

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.31- 3.43 (m, 3H), 3.71 (t, J = 5.0 Hz, 2H), 4.07 (d, J = 14.8 Hz, 1H), 4.17 (d, J = 14.8 Hz, 1H), 4.24-4.39 (m, 2H), 5.60 (brs, 1H), 7.24-7.47 (m, 7H), 7.84 (s, 1H). 178

1.10 (t, J = 7.0 Hz, 3H), 1.43 (d, J = 7.0 Hz, 3H), 2.44 (s, 3H), 3.32-3.42 (m, 3H), 3.71 (t, J = 5.0 Hz, 2H), 4.07 (d, J = 14.8 Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 4.25- 4.38 (m, 2H), 5.61 (brs, 1H), 7.26-7.39 (m, 6H), 7.83 (s, 1H).

TABLE 29 Example structural formula ¹H-NMR (CDCl₃) δ 179

1.08 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.30-3.41 (m, 3H), 3.70 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 15.1 Hz, 1H), 4.13 (d, J = 15.1 Hz, 1H), 4.24- 4.36 (m, 2H), 5.67 (brs, 1H), 6.90-6.98 (m, 2H), 7.21 (brs, 1H), 7.28-7.34 (m, 2H), 7.84 (s, 1H). 180

1.09 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.30-3.41 (m, 3H), 3.71 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.25- 4.37 (m, 2H), 5.68 (brs, 1H), 7.15-7.30 (m, 5H), 7.81 (s, 1H). 181

1.09 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 3.30-3.42 (m, 3H), 3.70 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 15.0 Hz, 1H), 4.14 (d, J = 15.0 Hz, 1H), 4.23- 4.38 (m, 2H), 5.63 (brs, 1H), 7.20 (brs, 1H), 7.26-7.30 (m, 3H), 7.47-7.50 (m, 2H), 7.83 (s, 1H). 182

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.37-3.44 (m, 3H), 3.72 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H), 4.25- 4.35 (m, 2H), 7.31 (m, 1H), 7.56- 7.59 (m, 2H), 7.70-7.73 (m, 2H), 7.84 (s, 1H). 183

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.31-3.43 (m, 3H), 3.74 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H), 4.28- 4.40 (m, 2H), 5.54 (brs, 1H), 7.18 (brs, 1H), 7.21-7.29 (m, 3H), 7.39 (m, 1H), 7.49 (s, 1H).

TABLE 30 Example structural formula ¹H-NMR (CDCl₃) δ 184

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 2.42 (s, 3H), 3.31-3.42 (m, 3H), 3.73 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.26- 4.38 (m, 2H), 5.56 (brs, 1H), 7.24 (brs, 1H), 7.26-7.30 (m, 3H), 7.46-7.50 (m, 3H). 185

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.31- 3.42 (m, 3H), 3.73 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.27-4.39 (m, 2H), 5.58 (brs, 1H), 7.23 (brs, 1H), 7.32 (d, J = 6.3 Hz, 1H), 7.39 (m, 1H), 7.45-7.51 (m, 3H), 7.57-7.59 (m, 2H). 186

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 3.31- 3.42 (m, 3H), 3.73 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.27-4.39 (m, 2H), 5.36 (brs, 1H), 7.20 (brs, 1H), 7.29 (d, J = 6.6 Hz, 1H), 7.42- 7.44 (m, 3H), 7.48-7.52 (m, 2H). 187

1.45 (t, J = 7.0 Hz, 3H), 1.48 (s, 6H), 3.99 (s, 2H), 4.20 (q, J = 7.0 Hz, 2H), 5.50 (brs, 1H), 7.13-7.18 (m, 2H), 7.28 (d, J = 6.6 Hz, 1H), 7.49 (d, J = 11.0 Hz, 1H), 7.52- 7.56 (m, 2H). 188

1.11 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 2.35 (s, 3H), 3.30-3.43 (m, 3H), 3.73 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H), 4.27-4.39 (m, 2H), 5.35 (brs, 1H), 7.09 (t, J = 8.8 Hz, 1H), 7.23 (brs, 1H), 7.34-7.39 (m, 3H), 7.48 (d, J = 10.8 Hz, 1H).

TABLE 31 Example structural formula ¹H-NMR (CDCl₃) δ 189

1.10 (t, J = 7.0 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 2.34 (s, 3H), 3.31-3.42 (m, 3H), 3.73 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.28-4.40 (m, 2H), 5.42 (brs, 1H), 7.22-7.31 (m, 5H), 7.49 (d, J = 10.7 Hz, 1H). 190

1.09 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.8 Hz, 3H), 2.33 (s, 3H), 3.31-3.41 (m, 3H), 3.71 (t, J = 5.0 Hz, 2H), 4.05 (d, J = 14.8 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H), 4.24-4.36 (m, 2H), 5.41 (brs, 1H), 7.07-7.26 (m, 5H), 7.60 (s, 1H).

Reference Example 55

To a solution of the compound (1.4 g, 5.0 mmol) obtained in the same manner as in Reference Examples 9 and 10 from 2-fluoro-5-bromo-nitrobenzene in tetrahydrofuran (30 mL) were added anhydrous sodium sulfate (3.8 g, 26.8 mmol), triethylamine (2.1 ml, 15.4 mmol) and (L)-alaninamide hydrochloride (1.9 g, 15.2 mmol), and the mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (0.33 g, 5.2 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column (dichloromethane:methanol=99:1-95:5) to give the object product (0.89 g, 51%).

Reference Example 56

To a solution of the compound (0.48 g, 1.3 mmol) obtained in Reference Example 55 in dichloroethane (10 mL) were added di-tert-butyl bicarbonate (1.4 g, 6.5 mmol) and diisopropylethylamine (0.33 ml, 1.95 mmol), and the mixture was stirred at 80° C. for 14 hr. Dichloromethane was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by silica gel column (dichloromethane:methanol=99:1-97:3) to give the object product (500 mg, 82%).

Reference Example 57

To a solution (3:1, 4 mL) of the compound (50 mg, 0.11 mmol) obtained in Reference Example 56 in aqueous acetonitrile were added 4-chlorophenylboranic acid (34 mg, 0.22 mmol), 3 mol/L aqueous sodium hydrogen carbonate solution (90 μl) and tetrakis(triphenylphosphine)palladium (13 mg, 0.00112 mmol), and the mixture was stirred at 85° C. for 5 hr under an argon atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to partition the residue. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel column (ethyl acetate alone) to give the object product (48 mg, 90%).

Example 191 N²-{[5-(4-chlorophenyl)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide hydrochloride

A solution (3 mL) of the compound (48 mg, 0.10 mmol) obtained in Reference Example 57 in hydrochloric acid-dioxane was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the resulting powder was washed with diethyl ether to give the object product (25 mg, 76%).

Example 192 N²-{[1-(2-ethoxyethyl)-5-(4-methoxyphenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide trifluoroacetate

To a solution (3 mL) of the compound (62 mg, 0.13 mmol) obtained in the above-mentioned Reference Example in dichloromethane was added trifluoroacetic acid (0.3 mL) under ice-cooling. The mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was concentrated and crystallized from diethyl ether to give the object product (48 mg, 76%).

Example 193-208

The compounds shown in Table 32 were prepared according to the methods described in the above-mentioned Reference Examples and Examples or methods analogous thereto.

The compounds were identified by LC/MS spectrum and retention time according to any of the following methods.

Analysis Conditions 1

detection instrument: LCMS/MS API2000 (manufactured by Applied Biosystems) column: Phenomenex Gemini C18 4.6×50 mm, 5 μm detection wavelength: 220 nm, 260 nm flow rate: 1.2 mL/min elution solvent composition: SOLUTION A: 0.05% aqueous TFA solution, 0.05% aqueous HCOOH solution or 10 mM aqueous ammonium acetate solution, SOLUTION B: acetonitrile gradient: 0-0.01 min B 10%, 0.01-1.50 min B 10% to 30%, 1.50-3.00 min B 30% to 90%, 3.00-4.00 min B 90%, 4.00-5.00 min B 90% to 10%

Analysis Conditions 2

detection instrument: LCMS/MS API2000 (manufactured by Applied Biosystems) column: Phenomenex Gemini C18 4.6×50 mm, 5 μm detection wavelength: 220 nm, 260 nm flow rate: 1 mL/min elution solvent composition: SOLUTION A: 0.05% aqueous TFA solution, 0.05% aqueous HCOOH solution or 10 mM aqueous ammonium acetate solution, SOLUTION B: acetonitrile gradient: 0-0.01 min B 5%, 0.01-1.00 min B 5%, 1.00-7.00 min B 5% to 50%, 7.00-10.00 min B 50% to 90%, 10.00-11.00 min B 90%, 11.00-12.00 min B 90% to 5%

TABLE 32

molecular retention analysis Example R salt weight m/e time conditions 191

HCl 400.1666 401.4 2.74 analysis conditions 1 MeCN—TFA 192

CF₃CO₂H 396.2161 397.4 2.61 analysis conditions 1 MeCN—TFA 193

HCl 366.2056 367.4 3.86 analysis conditions 1 MeCN—TFA 194

CF₃CO₂H 380.2212 381.4 6.29 analysis conditions 2 MeCN—TFA 195

HCl 394.2369 395.4 2.77 analysis conditions 1 MeCN—TFA 196

HCl 408.2525 409.4 2.84 analysis conditions 1 MeCN—TFA 197

HCl 384.1962 385.2 5.94 analysis conditions 2 MeCN—TFA 198

HCl 384.1962 385.2 5.94 analysis conditions 2 MeCN—TFA 199

HCl 402.1867 403.2 6.1  analysis conditions 2 MeCN—TFA 200

CF₃CO₂H 402.1867 403.4 2.75 analysis conditions 1 MeCN—TFA 201

HCl 420.1773 421.4 2.76 analysis conditions 1 MeCN—TFA 202

HCl 420.1773 421.2 6.25 analysis conditions 2 MeCN—TFA 203

HCl 410.2318 411.4 2.7  analysis conditions 1 MeCN—TFA 204

CF₃CO₂H 450.1879 451.2 2.78 analysis conditions 1 MeCN—TFA 205

CF₃CO₂H 434.193 435.4 2.79 analysis conditions 1 MeCN—TFA 206

HCl 420.1773 421.2 2.71 analysis conditions 1 MeCN—TFA 207

HCl 367.2008 368.6 5.99 analysis conditions 2 MeCN—TFA 208

HCl 391.2008 392.2 5.63 analysis conditions 2 MeCN—TFA

Reference Example 58

To a solution (25 mL) of iron (3.7 g, 66 mmol) and ammonium chloride (1.04 g, 19 mmol) in a mixed solvent (3:2:1) of tetrahydrofuran-methanol-water was added dropwise a solution (25 mL) of the compound (1.7 g, 6.9 mmol) obtained in Reference Example 18 in a mixed solvent (3:2:1) of tetrahydrofuran-methanol-water at 70° C. After 1.5 hr, the mixture was allowed to cool to room temperature, and the reaction mixture was filtered through celite. The filtrate was concentrated, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give the object product (1.32 g, 89%). The product was used for the next reaction without purification.

Reference Example 59

The object product was obtained in the same manner as in Reference Examples 4, 5, 55 and 56.

Reference Example 60

To a solution of the compound (60 mg, 0.14 mmol) obtained in Reference Example 59 and 4-methylphenylboronic acid (38 mg, 0.28 mmol) in n-butanol (2 mL) were added potassium phosphate (60 mg, 0.28 mmol), palladium acetate (3.2 mg, 0.014 mmol) and S-phos (11.6 mg, 0.0038 mmol), and the mixture was stirred at 100° C. for 14 hr under an argon atmosphere. After cooling, the reaction mixture was filtered through celite, and washed with methanol. The filtrate was concentrated, ethyl acetate was added thereto, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated. The residue was purified by silica gel column (ethyl acetate:hexane=65:35) to give the object product (43 mg, 52%).

Example 209 N²-{[3-(2-ethoxyethyl)-5-(4-methylphenyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-L-alaninamide hydrochloride

To a solution of the compound (34 mg) obtained in Reference Example 60 in dioxane (1 mL) was added 4 mol/L hydrochloric acid-dioxane (2 mL) under ice-cooling. The mixture was allowed to warm to room temperature, and stirred for 10 hr. The reaction mixture was concentrated, and the resulting powder was washed with diethyl ether to give the object product (28 mg, 95%).

Examples 210-226

The compounds shown in Table 33 were prepared according to the methods described in the above-mentioned Reference Examples and Examples or methods analogous thereto.

The compounds were identified by LC/MS spectrum and retention time under the conditions similar to those described above.

TABLE 33

molecular retention analysis Example R salt weight m/e time conditions 209

HCl 381.2165 382.3 6.15 analysis conditions 2 MeCN—TFA 210

HCl 367.2008 368.5 3.04 analysis conditions 1 MeCN—NH₄OAc 211

HCl 395.2321 396.4 2.79 analysis conditions 1 MeCN—TFA 212

HCl 409.2478 410.2 2.86 analysis conditions 1 MeCN—TFA 213

HCl 385.1914 386.4 3.12 analysis conditions 1 MeCN—NH₄OAc 214

HCl 385.1914 386.2 2.63 analysis conditions 1 MeCN—TFA 215

HCl 385.1914 386.2 2.63 analysis conditions 1 MeCN—TFA 216

HCl 403.182  404.2 2.6  analysis conditions 1 MeCN—TFA 217

HCl 403.182  404.4 2.71 analysis conditions 1 MeCN—TFA 218

HCl 421.1726 422.2 2.71 analysis conditions 1 MeCN—TFA 219

HCl 421.1726 422.1 6.25 analysis conditions 2 MeCN—TFA 220

HCl 397.2114 398.2 2.67 analysis conditions 1 MeCN—TFA 221

HCl 411.227  412.4 6.22 analysis conditions 2 MeCN—TFA 222

HCl 435.1882 436.6 2.79 analysis conditions 1 MeCN—TFA 223

HCl 451.1831 452.2 6.85 analysis conditions 2 MeCN—TFA 224

HCl 392.1961 393.4 2.61 analysis conditions 1 MeCN—TFA 225

HCl 421.1726 422   2.65 analysis conditions 1 MeCN—TFA 226

HCl 368.1961 369.6 5.34 analysis conditions 2 MeCN—TFA

Example 227-237

The compounds of Examples 227-237 shown in Table 34 and Table 35 were prepared in the same manner as in Reference Examples 18-20 and Example 79.

The compounds were identified by LC/MS spectrum and retention time under the conditions similar to those described above.

TABLE 34

molecular retention analysis Example R weight m/e time conditions 227

401.1863 402   2.64 analysis conditions 1 MeCN—TFA 228

417.1568 418   2.72 analysis conditions 1 MeCN—TFA 229

397.2114 398.2 2.67 analysis conditions 1 MeCN—TFA 230

419.1769 420.2 2.68 analysis conditions 1 MeCN—TFA 231

419.1769 420.2 2.67 analysis conditions 1 MeCN—TFA 232

437.1675 438   2.68 analysis conditions 1 MeCN—TFA

TABLE 35

molecular retention analysis Example R weight m/e time conditions 233

383.1758 384.2 2.71 analysis conditions 1 MeCN—TFA 234

379.2008 380.4 2.78 analysis conditions 1 MeCN—TFA 235

401.1663 402.2 2.71 analysis conditions 1 MeCN—TFA 236

401.1663 402.2 2.72 analysis conditions 1 MeCN—TFA 237

419.1569 419.9 2.75 analysis conditions 1 MeCN—TFA

The compounds shown in Tables 36-38 can be prepared according to the methods described in the above-mentioned Reference Examples and Examples or methods analogous thereto.

TABLE 36

No. R² 1

2

3

TABLE 37

No. R² 4

5

6

TABLE 38

No. R²  7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

Experimental Example 1 Inhibition Experiment of TTX Resistant Na Channel on Human SNS Gene-Expressing Cell

Human SNS gene-expressing cell is obtained by incorporating human SNS gene into Chinese hamster ovary cell (CHO-K1) and allowing stable expression. Since CHO-K1 cell does not inherently have a TTX resistant Na channel component, TTX resistant Na channel component of human SNS gene-expressing cell is SNS and the compound of the present invention is considered an SNS inhibitor.

1) Construction of Human SNS-Expressing Cell and Confirmation Of Expression of SNS Function

Full-length human SNS α subunit gene was incorporated into an expression plasmid (pcDNA3.1Zeo(+)) having a Zeocin resistance gene, and full-length Annexin II light chain gene was introduced into an expression plasmid (pcDNA3.1 (+)) containing a Neomycin resistance gene. These two genes were simultaneously introduced into CHO-K1 cell by using lipofectamine 2000, cultured in F-12 medium containing Neomycin and Zeocin, and a cell resistant to the both drugs, namely, a cell harboring the both genes, was selected. The two drug-resistance strain was subjected to limiting dilution twice, and the SNS gene-incorporating cell was cloned. Transgenic SNS was confirmed by RT-PCR, a TTX resistant component responsive to Na channel stimulation was detected by using a membrane potential sensitive fluorescent indicator, and functional expression of SNS was confirmed.

2) Pharmacological Effect on TTX Resistant Na Channel of Human SNS Gene-Expressing Cell

Using the human SNS-expressing cell obtained in the aforementioned 1, the SNS inhibitory action of the compound of the present invention was evaluated. To be specific, a test compound was added in advance to a human SNS-expressing cell, veratridine (50 μM), an Na channel stimulant, was added about 30 min later in the presence of TTX (1 μM), the membrane potencial was increased via the TTX resistant Na channel, and the suppressive action on the membrane potencial increase of the test compound was evaluated.

3) Pharmacological Evaluation Method

SNS inhibitory rate of the test compound was determined by the following calculation formula.

SNS inhibitory rate (%)=100×[(peak value by veratridine stimulation alone without test compound)−(peak value by veratridine stimulation with test compound)]/[(peak value by veratridine stimulation alone without test compound)−(standard value without stimulation)]

4) Test Results

The compounds obtained in the Examples were evaluated for an inhibitory action (SNS inhibitory rate) on TTX resistant Na channel of human SNS-expressing cell. As a result, the compound of the present invention was observed to show an SNS inhibitory action. The SNS inhibitory rate (%) when the compound concentration was 12.5 μM is shown in Tables 39-47.

TABLE 39 compound SNS inhibitory rate (%) Example 1 45.8 Example 2 8.4 Example 3 12.9 Example 4 66.8 Example 5 59.3 Example 6 77.8 Example 7 83.1 Example 8 90.4 Example 9 28.9 Example 10 16.3 Example 11 63.0 Example 12 17.0 Example 13 29.8 Example 14 16.4 Example 15 95.7 Example 16 96.2 Example 17 89.3 Example 18 14.2 Example 19 100 Example 20 7.2 Example 21 100 Example 22 16.4 Example 23 0.8 Example 24 5.8 Example 25 0.0 Example 26 26.6 Example 27 78.2 Example 28 27.4 Example 29 27.0 Example 30 31.5

TABLE 40 compound SNS inhibitory rate (%) Example 31 92.1 Example 32 91.2 Example 33 32.9 Example 34 6.7 Example 35 10.8 Example 36 0.4 Example 37 42.3 Example 38 48.8 Example 39 48.8 Example 40 95.8 Example 41 99.7 Example 42 76.7 Example 43 61.0 Example 44 84.9 Example 45 40.6 Example 46 95.5 Example 47 86.6 Example 48 96.7 Example 49 94.8 Example 50 86.8 Example 51 90.5 Example 52 89.7 Example 53 94.0 Example 54 95.7 Example 55 89.4 Example 56 82.2 Example 57 87.6 Example 58 71.2 Example 59 54.8 Example 60 75.7

TABLE 41 compound SNS inhibitory rate (%) Example 61 26.1 Example 62 93.8 Example 63 9.2 Example 64 82.7 Example 65 47.8 Example 66 16.8 Example 67 30.8 Example 68 16.0 Example 69 22.3 Example 70 11.2 Example 71 73.7 Example 72 7.3 Example 73 8.0 Example 74 58.2 Example 75 0.0 Example 76 18.8 Example 77 16.0 Example 78 22.2 Example 79 3.5 Example 80 2.5 Example 81 69.1 Example 82 30.7 Example 83 0.0 Example 84 76.8 Example 85 24.9 Example 86 8.3 Example 87 90.1 Example 88 83.5 Example 89 83.0 Example 90 96.1

TABLE 42 compound SNS inhibitory rate (%) Example 91 76.4 Example 92 66.7 Example 93 82.1 Example 94 63.9 Example 95 26.8 Example 96 84.8 Example 97 82.4 Example 98 69.8 Example 99 65.4 Example 100 72.1 Example 101 85.2 Example 102 96.3 Example 103 87.9 Example 104 83.6 Example 105 75.1 Example 106 86.4 Example 107 83.7 Example 108 85.3

TABLE 43 compound SNS inhibitory rate (%) Example 109 89.3 Example 110 9.8 Example 111 88.4 Example 112 0 Example 113 64.7 Example 114 6.5 Example 115 3.5 Example 116 33.2 Example 117 78.8 Example 118 64.5 Example 119 87.2 Example 120 92.4 Example 121 94.3 Example 122 100 Example 123 96.8 Example 124 87.8 Example 125 95.9 Example 126 56.9 Example 127 93.9 Example 128 85 Example 129 90.3 Example 130 42.1 Example 131 55.9 Example 132 86.4 Example 133 91.7 Example 134 95.7 Example 135 57.8 Example 136 28.7 Example 137 90.7 Example 138 93.1

TABLE 44 compound SNS inhibitory rate (%) Example 139 96 Example 140 97.5 Example 141 90.3 Example 142 47.9 Example 143 27.7 Example 144 6.1 Example 145 1.3 Example 146 19.7 Example 147 23.5 Example 148 17 Example 149 30.6 Example 150 45.6 Example 151 26.6 Example 152 8.9 Example 153 28.5 Example 154 11.2 Example 155 86.1 Example 156 71.2 Example 157 89.9 Example 158 86.1 Example 159 96.1 Example 160 97 Example 161 76.2 Example 162 67.3 Example 163 36.5 Example 164 3.7 Example 165 100 Example 166 62.7 Example 167 82.8 Example 168 20.2

TABLE 45 compound SNS inhibitory rate (%) Example 169 68.1 Example 170 14.2 Example 171 38.3 Example 172 50.9 Example 173 27.1 Example 174 33.4 Example 175 5.9 Example 176 68.8 Example 177 22.5 Example 178 16 Example 179 67.4 Example 180 4.5 Example 181 0 Example 182 0 Example 183 72.3 Example 184 87.9 Example 185 64.6 Example 186 55.6 Example 187 53.3 Example 188 87 Example 189 97.7 Example 190 34.3 Example 191 23.3 Example 192 11.9 Example 193 22.3 Example 194 19.7 Example 195 20.1 Example 196 23 Example 197 9.3 Example 198 10.2

TABLE 46 compound SNS inhibitory rate (%) Example 199 14.7 Example 200 22.4 Example 201 11.1 Example 202 26 Example 203 18.4 Example 204 0 Example 205 24.2 Example 206 14.5 Example 207 7 Example 208 0 Example 209 6.5 Example 210 2.1 Example 211 9.5 Example 212 20.6 Example 213 8.1 Example 214 0.2 Example 215 12.4 Example 216 0.7 Example 217 3.2 Example 218 12.5 Example 219 9.7 Example 220 12.2 Example 221 22 Example 222 10.1 Example 223 0 Example 224 0 Example 225 25.1 Example 226 14 Example 227 20.4 Example 228 31

TABLE 47 compound SNS inhibitory rate (%) Example 229 10.1 Example 230 33.2 Example 231 17.9 Example 232 16.1 Example 233 49.9 Example 234 94.3 Example 235 100 Example 236 71 Example 237 100

INDUSTRIAL APPLICABILITY

The novel bicyclic heterocyclic compound of the present invention can be used as a superior drug for the treatment or prophylaxis of pathology in which SNS is involved, specifically, diseases such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis and the like. 

1. A method of inhibiting SNS in a patient, which comprises administering an effective amount of a compound represented by formula (1):

wherein R¹ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms (R¹ can substitute the benzene ring or pyridine ring at any substitutable position thereon), L is a single bond, —O— or —CH₂O— (L can substitute the benzene ring or pyridine ring at any substitutable position thereon), R² is a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group, X is a carbon atom or a nitrogen atom, R³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered cycloalkenyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, R⁴ is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted 3- to 8-membered cycloalkyl group, R^(5a) and R^(5b) are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or R⁴ and R^(5a) are optionally bonded to form, together with the nitrogen atom that R⁴ is bonded to, a 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle (in this case, R^(5b) is a hydrogen atom), R⁶ and R⁷ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered cycloalkenyl group, a substituted or unsubstituted O-5 to 8-membered saturated aliphatic heterocyclic group, a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group, or R⁶ and R⁷ are optionally bonded to form, together with the nitrogen atom that they are bond to, a substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle, or a substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocycle (the saturated or unsaturated nitrogen-containing aliphatic heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 3 nitrogen atoms), or a pharmaceutically acceptable salt thereof, to the patient, whereupon SNS is inhibited in the patient.
 2. The method of claim 1, wherein the compound is represented by formula (2):

wherein R¹, R², R³, R⁴, R^(5a), R^(6b), R⁶, R⁷, L and X are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1, wherein the compound is represented by formula (3):

wherein R¹, R², R³, R⁴, R^(5a), R^(5b), R⁶, R⁷, L and X are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1, wherein R² is a substituted or unsubstituted phenyl group, or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1, wherein R³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, or a pharmaceutically acceptable salt thereof.
 6. The method of claim 1, wherein R⁶ and R⁷ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, or R⁶ and R⁷ are optionally bonded to form, together with the nitrogen atom that they are bond to, a substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle, or a substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocycle (the saturated or unsaturated nitrogen-containing aliphatic heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 3 nitrogen atoms), or a pharmaceutically acceptable salt thereof.
 7. The method of claim 1, wherein R⁴ is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.
 8. The method of claim 1, wherein R^(5a) and R^(5b) are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.
 9. The method of claim 1, wherein X is a carbon atom, or a pharmaceutically acceptable salt thereof.
 10. The method of claim 1, wherein R¹ is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof.
 11. The method of claim 1, wherein L is a single bond, or a pharmaceutically acceptable salt thereof.
 12. The method of claim 1, wherein L is —O—, or a pharmaceutically acceptable salt thereof.
 13. The method of claim 1, wherein L is —CH₂O—, or a pharmaceutically acceptable salt thereof.
 14. The method of claim 1, wherein the compound is selected from N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}glycinamide, N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide, N²-{[1-cyclopropyl-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[1-cyclobutyl-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[6-(4-chlorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[6-(4-fluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[6-(4-fluorophenoxy)-1-(3-methoxypropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[6-(2-chloro-4-fluorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[6-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[1-(2-ethoxyethyl)-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[1-ethyl-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[1-(3-methoxypropyl)-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[6-(4-methylphenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, N²-{[5-chloro-1-(2-ethoxyethyl)-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, and N²-{[5-chloro-6-(3,4-difluorophenyl)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, and a pharmaceutically acceptable salt thereof.
 15. The method of claim 1, wherein the compound is N²-{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide, or a pharmaceutically acceptable salt thereof.
 16. The method of claim 1, wherein the compound is N²-{[6-(2-chloro-4-fluorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
 17. The method of claim 1, wherein the compound is N²-{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
 18. The method of claim 1, wherein the compound is N²-{[1-(3-methoxypropyl)-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
 19. The method of claim 1, wherein the compound is N²-{[6-(4-methylphenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof. 